Transdermal delivery system comprising buprenorphine

ABSTRACT

The invention relates to transdermal therapeutic system for the transdermal administration of buprenorphine, comprising a buprenorphine-containing self-adhesive layer structure comprising A) a buprenoφhine-impermeable backing layer, and B) a buprenorphine-containing pressure-sensitive adhesive layer on said buprenorphine-impermeable backing layer, the adhesive layer comprising a) at least one polymer-based pressure-sensitive adhesive, b) an analgesically effective amount of buprenorphine base or a pharmaceutically acceptable salt thereof, and c) a carboxylic acid selected from the group consisting of oleic acid, linoleic acid and linolenic acid, levulinic acid and mixtures thereof, in an amount sufficient so that said analgesically effective amount of buprenorphine is solubilized therein to form a mixture, and the carboxylic acid buprenorphine mixture forms dispersed deposits in the said pressure-sensitive adhesive, wherein said buprenorphine-containing pressure-sensitive adhesive layer is the skin contact layer.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a transdermal therapeutic system (TTS)for the transdermal administration of buprenorphine, and processes ofmanufacture, uses thereof, and corresponding methods of treatmenttherewith.

BACKGROUND OF THE INVENTION

The active ingredient buprenorphine(5R,6R,7R,9R,13S,14S)-17-Cyclopropylmethyl-7-[(S)-3,3-dimethyl-2-hydroxybutan-2-yl]-6-methoxy-4,5-epoxy-6,14-ethanomorphinan-3-ol)is a partially synthetic opiate with high potency. Cancer patients maybe treated with daily doses of around 1 mg. Despite its rather highmolecular weight of 467.64 daltons, it is currently used for transdermaladministration. The commercial TTS product Norspan®, also known asBuTrans@, delivers buprenorphine to the skin sufficiently to treatpatients in pain for a time period of 7 days (about 168 hours) andallows therefore a use of the TTS over a time period of 7 days andallows in a fixed dosing regimen a once-weekly TITS exchange. This isspecifically beneficial in terms of convenience and patient compliance.Thus the overall efficacy of the pain medicament is enhanced. However,the long administration periods may cause problems with skin irritation,which in combination with the considerable size (i.e., area of release)of the TTS may be problematic. Also, the large amount of excess drug inthe TI'S necessary to sustain enough driving force for sustaining theappropriate drug delivery over the long period of time is costly and hasthe potential to be subject to illicit use.

It is therefore desirable to reduce the overall size (i.e., area ofrelease) of the TTS as well as the total amount of buprenorphine in theTTS before administration and also the amount remaining in the TTS afterproper use, the residual amount. Thereby, the amount of drug availablefor illicit use (before and after proper use), and the amount to bewasted after proper use are both reduced. US Patent Application No.2010/0119585 describes a certain TTS size and amount of drug reductionin comparison with the commercial TTS product Transtec® approved for anup-to-4 days administration regimen. Thus, the TTS needs to be replacedafter 4 days at the latest. It is recommended to change TranstecD twicea week always on the same days at specific times, e.g. Monday morningsand Thursday evenings.

For convenience reasons it is, however, desirable to maintain the onceweekly exchange mode (7 day dosing regimen) as, e.g., provided by thecommercial product Norspan® instead of the every three to four daysexchange mode as provided by, e.g., Transtec®.

All references and publications cited herein are hereby incorporated byreference in their enteritis for all purposes.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of certain embodiments of the present invention toprovide a transdermal therapeutic system for the transdermaladministration of buprenorphine (e.g., buprenorphine base), whichrequires a relatively small amount of buprenorphine (e.g., buprenorphinebase) contained therein.

It is an object of certain embodiments of the present invention toprovide a transdermal therapeutic system for the transdermaladministration of buprenorphine (e.g., buprenorphine base) whichrequires a relatively small area of release.

It is an object of certain embodiments of the present invention toprovide a transdermal therapeutic system for the transdermaladministration of buprenorphine (e.g., buprenorphine base) providing arelease suitable for providing pain relief for about 168 hours(corresponding to 7 days or one week).

These objects and others are accomplished by the present invention,which according to one aspect relates to a transdermal therapeuticsystem for the transdermal administration of buprenorphine (e.g.,buprenorphine base), comprising a buprenorphine (e.g., buprenorphinebase) containing self-adhesive layer structure comprising

-   -   A) a buprenorphine (e.g., buprenorphine base) impermeable        backing layer, and    -   B) a buprenorphine (e.g., buprenorphine base) containing        pressure-sensitive adhesive layer on said        buprenorphine-impermeable backing layer, the adhesive layer        comprising        -   a) at least one polymer-based pressure-sensitive adhesive,        -   b) an analgesically effective amount of buprenorphine base            or a pharmaceutically acceptable salt thereof, and        -   c) a carboxylic acid selected from the group consisting of            oleic acid, linoleic acid, linolenic acid, levulinic acid            and mixtures thereof, in an amount sufficient so that said            analgesically effective amount of buprenorphine (e.g.            buprenorphine base) is solubilized therein to form a            mixture, and the carboxylic acid buprenorphine mixture forms            dispersed deposits in said pressure-sensitive adhesive,            wherein said buprenorphine-containing pressure-sensitive            adhesive layer is the skin contact layer.

According to further aspects the invention relates to a method oftreating pain in a patient by applying a transdermal therapeutic systemin accordance with the invention to the skin of a patient, in particularto a method of treating pain in a patient by applying a transdermaltherapeutic system in accordance with the invention to the skin of saidpatient for more than about 96 hours (or for more than 4 days), or forabout 120 hours (or for 5 days), or for about 144 hours (or for 6 days)or for about 168 hours (or for 7 days or for one week).

According to one specific aspect, the invention relates to a method oftreating pain in a patient by applying to the skin of said patient forabout 168 hours (or for 7 days or for one week) a transdermaltherapeutic system, comprising a buprenorphine (e.g., buprenorphinebase) containing self-adhesive layer structure comprising

-   -   A) a buprenorphine (e.g., buprenorphine base) impermeable        backing layer, and    -   B) a buprenorphine (e.g., buprenorphine base) containing        pressure-sensitive adhesive layer on said        buprenorphine-impermeable backing layer, the adhesive layer        comprising        -   a) at least one polymer-based pressure-sensitive adhesive,        -   b) an analgesically effective amount of buprenorphine base            or a pharmaceutically acceptable salt thereof, and        -   c) a carboxylic acid selected from the group consisting of            oleic acid, linoleic acid, linolenic acid, levulinic acid            and mixtures thereof, in an amount sufficient so that said            analgesically effective amount of buprenorphine (e.g.,            buprenorphine base) is solubilized therein to form a            mixture, and the carboxylic acid buprenorphine mixture forms            dispersed deposits in said pressure-sensitive adhesive,            wherein said buprenorphine-containing pressure-sensitive            adhesive layer is the skin contact layer.

According to one aspect, the invention relates to a transdermaltherapeutic system for the transdermal administration of buprenorphinebase, comprising a buprenorphine base-containing self-adhesive layerstructure comprising

-   -   A) a buprenorphine base-impermeable backing layer, and    -   B) a buprenorphine base-containing pressure-sensitive adhesive        layer on said buprenorphine base-impermeable backing layer, the        adhesive layer comprising        -   a) at least one pressure-sensitive adhesive based on            polysiloxane,        -   b) an analgesically effective amount of buprenorphine base,            and        -   c) levulinic acid, in an amount sufficient so that said            analgesically effective amount of buprenorphine base is            solubilized therein to form a mixture, and the levulinic            acid buprenorphine base mixture forms dispersed deposits in            said pressure-sensitive adhesive,            wherein said buprenorphine base-containing            pressure-sensitive adhesive layer is the skin contact layer.

According to one aspect, the invention relates to a method of treatingpain in a patient by applying to the skin of said patient for about 168hours (or for 7 days or for one week) a transdermal therapeutic system,comprising a buprenorphine base-containing self-adhesive layer structurecomprising

-   -   A) a buprenorphine base-impermeable backing layer, and    -   B) a buprenorphine base-containing pressure-sensitive adhesive        layer on said buprenorphine base-impermeable backing layer, the        adhesive layer comprising        -   a) at least one pressure-sensitive adhesive based on            polysiloxane,        -   b) an analgesically effective amount of buprenorphine base,            and        -   c) levulinic acid, in an amount sufficient so that said            analgesically effective amount of buprenorphine base is            solubilized therein to form a mixture, and the levulinic            acid buprenorphine base mixture forms dispersed deposits in            said pressure-sensitive adhesive,            wherein said buprenorphine base-containing            pressure-sensitive adhesive layer is the skin contact layer.

According to one aspect, the invention relates to a transdermaltherapeutic system for the transdermal administration of buprenorphine,comprising a buprenorphine-containing self-adhesive layer structurecomprising

-   -   A) a buprenorphine-impermeable backing layer, and    -   B) a buprenorphine-containing pressure-sensitive adhesive layer        on said buprenorphine-impermeable backing layer, the adhesive        layer comprising        -   a) at least one polymer-based pressure-sensitive adhesive,        -   b) an analgesically effective amount of buprenorphine base            or a pharmaceutically acceptable salt thereof, and        -   c) a carboxylic acid selected from the group consisting of            oleic acid, linoleic acid, linolenic acid, levulinic acid            and mixtures thereof, in an amount sufficient so that said            analgesically effective amount of buprenorphine is            solubilized therein to form a mixture, and the carboxylic            acid buprenorphine mixture forms dispersed deposits in said            pressure-sensitive adhesive,            wherein said buprenorphine-containing pressure-sensitive            adhesive layer is the skin contact layer and contains more            than about 0.55 mg/cm² or more than 0.6 mg/cm² of            buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.

According to one aspect, the invention relates to a method of treatingpain in a patient by applying to the skin of said patient for about 168hours a transdermal therapeutic system for the transdermaladministration of buprenorphine, comprising a buprenorphine-containingself-adhesive layer structure comprising

-   -   A) a buprenorphine-impermeable backing layer, and    -   B) a buprenorphine-containing pressure-sensitive adhesive layer        on said buprenorphine-impermeable backing layer, the adhesive        layer comprising        -   a) at least one polymer-based pressure-sensitive adhesive,        -   b) an analgesically effective amount of buprenorphine base            or a pharmaceutically acceptable salt thereof, and        -   c) a carboxylic acid selected from the group consisting of            oleic acid, linoleic acid and linolenic acid, levulinic acid            and mixtures thereof, in an amount sufficient so that said            analgesically effective amount of buprenorphine is            solubilized therein to form a mixture, and the carboxylic            acid buprenorphine mixture forms dispersed deposits in the            said pressure-sensitive adhesive,            wherein said buprenorphine-containing pressure-sensitive            adhesive layer is the skin contact layer and contains more            than about 0.55 mg/cm² or more than 0.6 mg/cm² of            buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.

According to one aspect, the invention relates to a transdermaltherapeutic system for the transdermal administration of buprenorphinebase, comprising a buprenorphine base-containing self-adhesive layerstructure comprising

-   -   A) a buprenorphine base-impermeable backing layer, and    -   B) a buprenorphine base-containing pressure-sensitive adhesive        layer on said buprenorphine base-impermeable backing layer, the        adhesive layer comprising        -   a) at least one pressure-sensitive adhesive based on            polysiloxane,        -   b) an analgesically effective amount of buprenorphine base,            and        -   c) levulinic acid, in an amount sufficient so that said            analgesically effective amount of buprenorphine base is            solubilized therein to form a mixture, and the levulinic            acid buprenorphine base mixture forms dispersed deposits in            the said pressure-sensitive adhesive,            wherein said buprenorphine base-containing            pressure-sensitive adhesive layer is the skin contact layer            and contains more than about 0.55 mg/cm² or more than 0.6            mg/cm² buprenorphine base.

According to one aspect, the invention relates to a method of treatingpain in a patient by applying to the skin of said patient for about 168hours (or for 7 days or for one week) a transdermal therapeutic systemcomprising a buprenorphine base-containing self-adhesive layer structurecomprising

-   -   A) a buprenorphine base-impermeable backing layer, and    -   B) a buprenorphine base-containing pressure-sensitive adhesive        layer on said buprenorphine base-impermeable backing layer, the        adhesive layer comprising        -   a) at least one pressure-sensitive adhesive based on            polysiloxane,        -   b) an analgesically effective amount of buprenorphine base,            and        -   c) levulinic acid, in an amount sufficient so that said            analgesically effective amount of buprenorphine base is            solubilized therein to form a mixture, and the levulinic            acid buprenorphine base mixture forms dispersed deposits in            the said pressure-sensitive adhesive,            wherein said buprenorphine base-containing            pressure-sensitive adhesive layer is the skin contact layer            and contains more than about 0.55 mg/cm² or more than 0.6            mg/cm² buprenorphine base.

According to one aspect, the invention relates to a set of two to fivedifferent transdermal therapeutic systems for the transdermaladministration of buprenorphine base selected from five differenttransdermal therapeutic systems, a first, a second, a third, a forth anda fifth transdermal therapeutic system, each of the five differenttransdermal therapeutic systems comprising a buprenorphine-containingself-adhesive layer structure comprising

-   -   A) a buprenorphine base-impermeable backing layer, and    -   B) a buprenorphine base-containing pressure-sensitive adhesive        layer on said buprenorphine base-impermeable backing layer, the        adhesive layer comprising        -   a) at least one pressure-sensitive adhesive based on            polysiloxanes,        -   b) an analgesically effective amount of buprenorphine base,            and        -   c) levulinic acid, in an amount sufficient so that said            analgesically effective amount of buprenorphine base is            solubilized therein to form a mixture, and the levulinic            acid buprenorphine base mixture forms dispersed deposits in            the said pressure-sensitive adhesive,            wherein,            the first transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 1 cm²            to about 4.8 cm² and contains from about 1 mg to about 4 mg            buprenorphine base;            the second transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 3 cm²            to about 9.5 cm² and contains an amount of from about 3.5 mg            to about 8 mg buprenorphine base; and            the third transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 6 cm²            to about 19 cm² and contains from about 6.5 mg to about 16            mg buprenorphine base; and            the fourth transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 12            cm² to about 28.5 cm² and contains from about 11.5 mg to            about 24 mg buprenorphine base; and            the fifth transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 16            cm² to about 38 cm² and contains from about 15 mg to about            32 mg buprenorphine base,            wherein the five different transdermal therapeutic systems            have increasing areas of release and amounts of            buprenorphine from the first to the fifth transdermal            therapeutic system, in particular for use in method of            treating pain by applying one of said transdermal            therapeutic systems for about 168 hours on the skin of a            patient.

According to one aspect, the invention relates to a transdermaltherapeutic system comprising buprenorphine for the transdermaladministration of buprenorphine selected from:

a first transdermal therapeutic system providing a size of the area ofrelease ranging from about 1 cm² to about 4.8 cm² and containing anamount of said buprenorphine from 1 mg to about 4 mg buprenorphine baseor an equimolar amount of a pharmaceutically acceptable salt thereof andproviding a mean AUCt of more than 8,000 pg·hr/ml over about 168 hoursof administration after a single-dose administration to a subjectpopulation;a second transdermal therapeutic system providing a size of the area ofrelease ranging from about 3 cm² to about 9.5 cm² and containing anamount of said buprenorphine from about 3.5 mg to about 8 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a mean AUCt of more than 16,000pg·hr/ml over about 168 hours of administration after a single-doseadministration to a subject population; anda third transdermal therapeutic system providing a size of the area ofrelease ranging from about 6 cm² to about 19 cm² and containing anamount of said buprenorphine from about 6.5 mg to about 16 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a mean AUCt of more than 32,000pg·hr/ml over about 168 hours of administration after a single-doseadministration to a subject population; anda fourth transdermal therapeutic system providing a size of the area ofrelease ranging from about 12 cm² to about 28.5 cm² and containing anamount of said buprenorphine from about 11.5 mg to about 24 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a mean AUCt of more than 48,000pg·hr/ml over about 168 hours of administration after a single-doseadministration to a subject population; anda fifth transdermal therapeutic system providing a size of the area ofrelease ranging from about 16 cm² to about 38 cm² and containing anamount of said buprenorphine from about 15 mg to about 32 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a mean AUCt of more than 64,000pg·hr/ml over about 168 hours of administration after a single-doseadministration to a subject population, in particular for use in methodof treating pain by applying said selected transdermal therapeuticsystem for about 168 hours on the skin of a patient.

According to one aspect, the invention relates to a transdermaltherapeutic system comprising buprenorphine for the transdermaladministration of buprenorphine selected from:

a first transdermal therapeutic system providing a size of the area ofrelease ranging from about 1 cm² to about 4.8 cm² and containing anamount of said buprenorphine from 1 mg to about 4 mg buprenorphine baseor an equimolar amount of a pharmaceutically acceptable salt thereof andproviding a nominal mean release rate of about 5 μg/hr over about 168hours of administration;a second transdermal therapeutic system providing a size of the area ofrelease ranging from about 3 cm² to about 9.5 cm² and containing anamount of said buprenorphine from about 3.5 mg to about 8 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a nominal mean release rate ofabout 10 μg/hr over about 168 hours of administration; anda third transdermal therapeutic system providing a size of the area ofrelease ranging from about 6 cm² to about 19 cm² and containing anamount of said buprenorphine from about 6.5 mg to about 16 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a nominal mean release rate ofabout 20 μg/hr over about 168 hours of administration; anda fourth transdermal therapeutic system providing a size of the area ofrelease ranging from about 12 cm² to about 28.5 cm² and containing anamount of said buprenorphine from about 11.5 mg to about 24 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a nominal mean release rate ofabout 30 μg/hr over about 168 hours of administration; anda fifth transdermal therapeutic system providing a size of the area ofrelease ranging from about 16 cm² to about 38 cm² and containing anamount of said buprenorphine from about 15 mg to about 32 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a nominal mean release rate ofabout 40 μg/hr over about 168 hours of administration, in particular foruse in method of treating pain by applying said selected transdermaltherapeutic system for about 168 hours on the skin of a patient.

According to one aspect, the invention relates to a set of transdermaltherapeutic systems including at least two transdermal therapeuticsystems selected from the first, second, third, fourth and fifthtransdermal therapeutic systems as described in the previous paragraphs.

According to one aspect, the invention relates to a method of treatingpain in a patient by selecting for said patient the appropriatetransdermal therapeutic system from the first, second, third, fourth andfifth transdermal therapeutic system as described in the previousparagraphs and subsequently applying said selected transdermaltherapeutic system on the skin of said patient for about 168 hours.

According to one aspect, the invention relates to a transdermaltherapeutic system comprising buprenorphine for the transdermaladministration of buprenorphine, wherein buprenorphine is present in theform of buprenorphine base and providing a non-cumulative release ofbuprenorphine base as measured in a Franz diffusion cell with dermatomedhuman skin of

2 μg/cm² to 10 μg/cm² in the first 8 hours,20 μg/cm² to 80 μg/cm² from hour 8 to hour 24,20 μg/cm² to 80 μg/cm² from hour 24 to hour 32,30 μg/cm² to 120 μg/cm² from hour 32 to hour 48,40 μg/cm² to 150 μg/cm² from hour 48 to hour 72,100 μg/cm² to 300 μg/cm² from hour 72 to hour 144, and30 μg/cm² to 100 μg/cm² from hour 144 to hour 168, in particular for usein method of treating pain by applying the transdermal therapeuticsystem for about 168 hours on the skin of a patient.

According to one aspect, the invention relates to a transdermaltherapeutic system comprising buprenorphine for the transdermaladministration of buprenorphine, wherein buprenorphine is present in theform of buprenorphine base and providing a non-cumulative release ofbuprenorphine base as measured in a Franz diffusion cell with dermatomedhuman skin of

2 μg/cm² to 10 μg/cm² in the first 8 hours,20 μg/cm² to 80 μg/cm² from hour 8 to hour 24,20 μg/cm² to 80 μg/cm² from hour 24 to hour 32,30 μg/cm² to 120 μg/cm² from hour 32 to hour 48,40 μg/cm² to 150 μg/cm² from hour 48 to hour 72,100 μg/cm² to 300 μg/cm² from hour 72 to hour 144, and30 μg/cm² to 100 μg/cm² from hour 144 to hour 168, andcomprising a buprenorphine base-containing self-adhesive layer structurecomprising

-   -   A) a buprenorphine base-impermeable backing layer, and    -   B) a buprenorphine base-containing pressure-sensitive adhesive        layer on said buprenorphine base-impermeable backing layer, the        adhesive layer comprising        -   a) at least one polymer-based pressure-sensitive adhesive,        -   b) an analgesically effective amount of buprenorphine base,            and optionally        -   c) a carboxylic acid selected from the group consisting of            oleic acid, linoleic acid, linolenic acid, levulinic acid            and mixtures thereof, in an amount sufficient so that said            analgesically effective amount of buprenorphine base is            solubilized therein to form a mixture, and the carboxylic            acid buprenorphine base solution forms dispersed deposits in            the said pressure-sensitive adhesive,            wherein said buprenorphine base-containing            pressure-sensitive adhesive layer is the skin contact layer,            in particular for use in method of treating pain by applying            the transdermal therapeutic system for about 168 hours on            the skin of a patient.

Within the meaning of this invention, the term “transdermal therapeuticsystem” (or TTS) refers to the entire individual unit that is applied tothe skin of a patient, and which comprises the buprenorphine-containingself-adhesive layer structure and optionally an additional largeractive-free self-adhesive layer structure on top of thebuprenorphine-containing self-adhesive layer structure, which TTSprovides the percutaneous delivery of the active buprenorphine to thepatient. During storage, such a TTS is normally located on aredetachable protective layer from which it is removed immediatelybefore application to the surface of the patient's skin. A TTS protectedthis way may be stored in a blister pack or a side sealed bag.

Within the meaning of this invention, the term “buprenorphine-containingself-adhesive layer structure” refers to the active agent-containingstructure providing the area of release of the active agent.

Within the meaning of this invention, “polymer-based pressure-sensitiveadhesive” refers to a pressure-sensitive adhesive containing from 75% to100% of said polymer based on the dry weight of the pressure-sensitiveadhesive, e.g., 75% to 100% of polysiloxane. According to certainembodiments the pressure-sensitive adhesive contains from 80% to 100%,or from 85% to 100%, or from 90% to 100%, or from 95% to 100% of thepolymer (e.g., polysiloxane) based on the dry weight of the pressuresensitive adhesive. A pressure-sensitive adhesive is in particular amaterial that adheres with finger pressure, is permanently tacky, exertsa strong holding force and should be removable from smooth surfacewithout leaving a residue. Examples of useful pressure-sensitiveadhesives based on polysiloxane which are commercially available includethe standard Bio-PSA series (7-4400, 7-4500 and 7-4600 series), theamine compatible (endcapped) Bio-PSA series (7-4100, 7-4200 and 7-4300series) and the Soft Skin Adhesives series (7-9800) manufactured by DowCorning. Preferred pressure-sensitive adhesives based on polysiloxaneare heptane-solvated pressure-sensitive adhesives including BIO-PSA7-4201, BIO-PSA 7-4301, BIO-PSA 7-4501.

Within the meaning of this invention, the term “additional larger activeagent-free self-adhesive layer structure” refers to a self-adhesivelayer structure that is free of active agent and larger than the activeagent-containing structure and providing additional area adhering to theskin, but no area of release of the active agent, and enhancing therebythe overall adhesive properties of the TS.

Within the meaning of this invention, the term “buprenorphine-containingpressure-sensitive adhesive layer” and “matrix layer” have the samemeaning and refer to the layer containing the active in a matrix-typestructure of active in-adhesive.

Within the meaning of this invention, the term “skin contact layer”refers to the part of the TTS which is in direct contact with the skinof the patient during administration and is located in/co-extensive withthe buprenorphine-containing self-adhesive layer structure. The sizes ofthe “skin contact layer” and the buprenorphine-containing self-adhesivelayer structure are co-extensive and correspond to the area of release.

Within the meaning of this invention, the term “deposit” refers todistinguishable, e.g., visually distinguishable, areas within thepressure-sensitive adhesive. Such deposits are e.g., droplets. Depositsthat are visually distinguishable may be identified by use of amicroscope.

Within the meaning of this invention, the parameter “mean cumulativeskin permeation rate” is provided in μg/cm²-hr and is calculated fromthe cumulative release as measured by in vitro experiments carried outwith the Franz diffusion cell over the total time period of release,e.g., 168 hours, in μg/cm² divided by the hours corresponding to saidtotal time period of release, e.g., 168 hours.

Within the meaning of this invention, the parameter “mean non-cumulativeskin permeation rate” is provided in μg/cm²-hr and is calculated fromthe non-cumulative release of a certain sample interval as measured in aFranz diffusion cell in μg/cm² divided by the hours of said sampleinterval.

Within the meaning of this invention, the parameter “cumulative release”is provided in g/cm² and relates to the total amount released over thetotal time period of release, e.g., 168 hours, as measured in a Franzdiffusion cell. The value is a mean value of at least 3 experiments.

Within the meaning of this invention, the parameter “non-cumulativerelease” is provided in μg/cm² and relates to the amount released in asample interval at certain elapsed time within the total time period ofrelease, e.g., hour 16 of release corresponding to a sample interval of8 hours from hour 8 to hour 16 of release within 168 hours of total timeperiod of release, as measured in a Franz diffusion cell. The value is amean value of at least 3 experiments.

Within the meaning of this invention, the parameter “mean release rate”refers to the mean release rate in μg/hr over the period ofadministration (e.g., 7 days) by which the active agent permeatesthrough the human skin into the blood system and is based on the AUCobtained over said period of administration in a clinical study.

Within the meaning of this invention, the parameter “nominal meanrelease rate” refers to an assigned mean release rate determined bycomparison with the commercial reference product BuTrans® which isapplied for 7 days to the skin of the subjects and of which mean releaserates are publicly available from the package insert. The correspondingknown nominal mean release rate of the 25 cm² area of release BuTrans®reference TTS containing 20 mg buprenorphine is 20 μg/hr. The meanrelease rate is proportional to the size of the area of release of a TSand may be used to distinguish TTSs by the dosage strength. The BuTrans®TTS with half the size (i.e. 12.5 cm² area of release) and containing 10mg of buprenorphine provides the known nominal mean release rate of 10μg/hr. The BuTrans® TTS with a size of 6.25 cm² area of release andcontaining 5 mg of buprenorphine provides the known nominal mean releaserate of 5 μg/hr. Accordingly, it can be assumed that a corresponding TTSwith a size of 50 cm² area of release and containing 40 mg ofbuprenorphine provides a nominal mean release rate of 40 μg/hr, and acorresponding TTS with a size of 37.5 cm area of release and containing30 mg of buprenorphine provides a nominal mean release rate of 30 μg/hr.The nominal mean release rates are assigned to the TTSs in accordancewith the invention based on bioequivalence considerations by at leastcomparing the mean AUCt of the reference TTS BuTrans® with the mean AUCtof the TTSs in accordance with the invention obtained in the sameclinical study.

Within the meaning of this invention, the meaning of “by applying to theskin of said patient for about 168 hours” corresponds to “by applying tothe skin of said patient for about 7 days or for one week” and refers toa once a week exchange mode or dosing regimen. Likewise, about 96 hourscorrespond to 4 days, about 120 hours correspond to 5 days and about 144hours correspond to 6 days. The term “applying to the skin of a patientfor a certain period of time” has the same meaning as “administrationfor a certain period of time”.

Within the meaning of this invention, the term “patient” refers to asubject who has presented a clinical manifestation of a particularsymptom or symptoms suggesting the need for treatment, who is treatedpreventatively or prophylactically for a condition, or who has beendiagnosted with a condition to be treated.

If not indicated otherwise “%” refers to weight-%.

Within the meaning of this invention, the term “active”, “active agent”,and the like, as well as the term “buprenorphine” refers tobuprenorphine base or a pharmaceutically acceptable salt thereof. Unlessotherwise indicated the amounts of buprenorphine in the TTS relate tothe amount of buprenorphine before administration of the TTS. Theamounts of buprenorphine in the TTS after administration are referred toas residual amounts.

Within the meaning of this invention, values and ranges specifying thesize of the area of release and the amount of buprenorphine contained inthe transdermal therapeutic system are mean values of at least 3measurements.

Within the meaning of this invention the term “pharmacokineticparameters” refers to parameters describing the blood plasma curve, e.g.Cmax, AUCt and AUCINF obtained in a clinical study, e.g. by single-doseadministration of the active agent TTS, e.g. the buprenorphine base TTSto healthy human subjects. The pharmacokinetic parameters of theindividual subjects are summarized using arithmetic and geometric means,e.g. a mean Cmax, a mean AUCt and a mean AUCINF, and additionalstatistics such as the respective standard deviations and standarderrors, the minimum value, the maximum value, and the middle value whenthe list of values is ranked (Median). In the context of the presentinvention, pharmacokinetic parameters, e.g. the mean Cmax, the mean AUCtand the mean AUCINF refer to geometric mean values if not indicatedotherwise. It cannot be precluded that the absolute mean values obtainedfor a certain TTS in a clinical study vary to a certain extend fromstudy to study. To allow a comparison of absolute mean values betweenstudies, a reference formulation, e.g. the commercial reference productBuTrans® or in the future any product based on the invention, may beused as internal standard. A comparison of the AUC per area of release,e.g. the mean AUCt per area of release of the respective referenceproduct in the earlier and later study can be used to obtain acorrection factor to take into account differences from study to study.

Clinical studies according to the present invention refer to studiesperformed in full compliance with the International Conference forHarmonization of Clinical Trials (ICH) and all applicable local GoodClinical Practices (GCP) and regulations.

Within the meaning of this invention, the term “healthy human subject”refers to a male or female subject with a body weight ranging from 55 kgto 100 kg and a body mass index (BMI) ranging from 18 to 29 and normalphysiological parameters, such as blood pressure, etc. Healthy humansubjects for the purposes of the present invention are selectedaccording to inclusion and exclusion criteria which are based on and inaccordance with recommendations of the ICH.

Within the meaning of this invention, the term “subject population”refers to at least ten individual healthy human subjects.

Within the meaning of this invention, the term “geometric mean” refersto the mean of the log transformed data backtransformed to the originalscale.

Within the meaning of this invention, the term “arithmetic mean” refersto the sum of all values of observation divided by the total number ofobservations.

Within the meaning of this invention, the parameter “AUC” corresponds tothe area under the plasma concentration-time curve. The AUC value isproportional to the amount of active agent absorbed into the bloodcirculation in total and is hence a measure for the bioavailability.

Within the meaning of this invention, the parameter “AUCt” is providedin pg·hr/ml and relates to the area under the plasma concentration-timecurve from hour 0 to the last measurable plasma concentration and iscalculated by the linear trapezoidal method.

Within the meaning of this invention, the parameter “mean AUCt per areaof release” is provided in pg·hr/ml-cm² and is calculated from thegeometric mean AUCt as determined for a certain TTS in pg·hr/ml dividedby the area of release of said TTS.

Within the meaning of this invention, the parameter “AUCINF” is providedin pg·hr/ml and relates to the area under the plasma concentration-timecurve extrapolated to infinity and is calculated using the formula:

${AUCINF} = {{AUCt} + \frac{CLast}{LambdaZ}}$

where CLast is the last measurable plasma concentration and LambdaZ isthe apparent terminal phase rate constant.

Within the meaning of this invention, the parameter “Cmax” is providedin pg/ml and and relates to the maximum observed blood plasmaconcentration of the active agent.

Within the meaning of this invention, the parameter “tmax” is providedin hr and relates to the time point at which the Cmax value is reached.In other words, tmax is the time point of the maximum observed plasmaconcentration.

Within the meaning of this invention, the parameter “LambdaZ” isprovided in 1/hr and relates to the apparent terminal phase rateconstant, where LambdaZ is the magnitude of the slope of the linearregression of the log concentration versus time profile during theterminal phase.

Within the meaning of this invention, the parameter “t1/2Z” is providedin hr and relates to the apparent plasma terminal phase half-life and iscommonly determined as t1/2Z=(ln2)/LambdaZ.

Within the meaning of this invention, the term “mean plasmaconcentration” is provided in pg/ml and is a mean of the individualplasma concentrations of active agent, e.g. buprenorphine base, at eachpoint in time.

Within the meaning of this invention, the term “bioequivalent” isdefined to refer to a TTS that provides geometric mean values of Cmax,AUCt, and AUCINF for buprenorphine, wherein the 90% confidence intervalsestimated for the ratio 10 test/reference fall within the range of80.00% to 125.00%.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the mean non-cumulative skin permeation rate for Examples1 to 4 and Norspan®.

FIG. 2 depicts the mean non-cumulative skin permeation rate of thetransdermal therapeutic systems. The area of release of the transdermaltherapeutic systems according to Examples 1 to 4 being 10 cm² and thearea of release for Norspan® being 25 cm². The amount of buprenorphinebase for Examples 1 to 4 being 12 mg and the amount of buprenorphinebase for Norspan® being 20 mg.

FIG. 3 depicts the mean non-cumulative skin permeation rate forComparative Example 5 and Norspan®.

FIG. 4 depicts the mean non-cumulative skin permeation rate of the ofthe transdermal therapeutic systems. The area of release of thetransdermal therapeutic system according to Comparative Example 5 being15 cm² and the area of release for Norspan® being 25 cm². The amount ofbuprenorphine base for Comparative Example 5 being 6.75 mg and theamount of buprenorphine base for Norspan® being 20 mg.

FIG. 5 depicts the mean plasma concentration for Examples 1 and 2,Comparative Example 5 and BuTrans®. The area of release of thetransdermal therapeutic systems according to Examples 1 and 2 being 10cm², the area of release of the transdermal therapeutic systemsaccording to Comparative Example 5 being 15 cm² and the area of releasefor BuTrans® being 25 cm². The amount of buprenorphine base for Examples1 and 2 being 12 mg, the amount of buprenorphine base for ComparativeExample 5 being 6.75 mg and the amount of buprenorphine base forBuTrans® being 20 mg.

DETAILED DESCRIPTION TTS Structure

According to the invention wherein the structure is concerned, the TTSfor the transdermal administration of buprenorphine comprises abuprenorphine-containing self-adhesive layer structure comprising

-   -   A) a buprenorphine-impermeable backing layer, and    -   B) a buprenorphine-containing pressure-sensitive adhesive layer        on said buprenorphine-impermeable backing layer, the adhesive        layer comprising        -   a) at least one polymer-based pressure-sensitive adhesive,        -   b) an analgesically effective amount of buprenorphine base            or a pharmaceutically acceptable salt thereof, and        -   c) a carboxylic acid selected from the group consisting of            oleic acid, linoleic acid, linolenic acid, levulinic acid            and mixtures thereof, in an amount sufficient so that said            analgesically effective amount of buprenorphine is            solubilized therein to form a mixture, and the carboxylic            acid buprenorphine mixture forms dispersed deposits in the            said pressure-sensitive adhesive,            wherein said buprenorphine-containing pressure-sensitive            adhesive layer is the skin contact layer.

According to an aspect of the invention the TTS for the transdermaladministration of buprenorphine base comprises a buprenorphinebase-containing self-adhesive layer structure comprising

-   -   A) a buprenorphine base-impermeable backing layer, and    -   B) a buprenorphine base-containing pressure-sensitive adhesive        layer on said buprenorphine base-impermeable backing layer, the        adhesive layer comprising        -   a) at least one pressure-sensitive adhesive based on            polysiloxane,        -   b) an analgesically effective amount of buprenorphine base            or a pharmaceutically acceptable salt thereof and        -   c) levulinic acid in an amount sufficient so that said            analgesically effective amount of buprenorphine base is            solubilized therein to form a mixture, and the levulinic            acid buprenorphine base mixture forms dispersed deposits in            the said pressure-sensitive adhesive,            wherein said buprenorphine base-containing            pressure-sensitive adhesive layer is the skin contact layer.            Hence, the TTS according to the invention allows no            additional layer in between the buprenorphine            base-containing pressure-sensitive adhesive layer and the            skin.

According to certain preferred embodiments, the invention relates to aTTS with a buprenorphine-containing self-adhesive layer structureconsisting essentially of:

-   -   A) a buprenorphine base-impermeable backing layer, and    -   B) a buprenorphine base-containing pressure-sensitive adhesive        layer on said buprenorphine base-impermeable backing layer, the        adhesive layer comprising        -   a) at least one pressure-sensitive adhesive based on            polysiloxane,        -   b) an analgesically effective amount of buprenorphine base            or a pharmaceutically acceptable salt thereof, and        -   c) levulinic acid, in an amount sufficient so that said            analgesically effective amount of buprenorphine base is            solubilized therein to form a mixture, and the levulinic            acid buprenorphine base mixture forms dispersed deposits in            the said pressure-sensitive adhesive.

According to certain embodiments of the invention, the TTS comprises inaddition to the buprenorphine-containing self-adhesive layer structureattached thereto a larger active agent-free self-adhesive layerstructure, e.g., a peripheral adhesive or overlying adhesive, forenhancing the adhesive properties of the overall transdermal therapeuticsystem. Said active agent-free self-adhesive layer structure comprisesalso a backing layer, e.g., beige colored, and in this case an activeagent free pressure-sensitive adhesive layer of polymer-basedpressure-sensitive adhesive, e.g., based on polyacrylates orpolysiloxane. The area of said second active agent agent-freeself-adhesive layer structure adds to the overall size of the TTS butdoes not add to the area of release. The pressure-sensitive adhesive inthe active agent containing and the active agent-free self-adhesivelayer structures may be the same or different. If the adhesive in theactive agent free self-adhesive layer is different from that of thebuprenorphine-containing layer, then pressure-sensitive adhesivesselected from the group of poly acrylate based or poly isobutylene basedpressure-sensitive adhesives can be used, and poly acrylate basedpressure-sensitive adhesives are preferred, in particularpressure-sensitive adhesives based on an acrylate-vinylacetate polymer,e.g., such as those available from Henkel under the tradename Duro Tak®,e.g., Duro Tak® 387 2051. Such pressure-sensitive adhesives are providedin an organic solution of ethyl acetate and heptane. Suchpressure-sensitive adhesives provide a 180° Peel at 20 minutes of atleast about 20 N/25 mm, and at 24 minutes of at least about 25 N/25 cm,and at one week of at least about 30 N/25 mm and a Loop tack of at least15 N/25 mm², or of at least 20 N/25 mm², or of at least 22 N/25 mm².

Active Agent

The TTS according to the invention comprises an analgesically effectiveamount of buprenorphine base or an equimolar amount of apharmaceutically acceptable salt thereof. Pharmaceutically acceptablesalts may be selected from those known in the art, such as thehydrochloride, sulphate, phosphate, tartrate, maleinate, oxalate,acetate and lactate salts. According to a preferred embodiment of theinvention the active agent is buprenorphine base.

An analgesically effective amount may vary from about 1 mg to about 50mg, in particular from about 2 mg to about 30 mg of buprenorphine baseor an equimolar amount of a pharmaceutically acceptable salt, or fromabout 2 mg to about 25 mg of buprenorphine base or an equimolar amountof a pharmaceutically acceptable salt thereof. According to certainembodiments, the TTS contains according to five different dosages fromabout 1 mg to about 4 mg, or from about 3.5 mg to about 8 mg, or fromabout 6.5 mg to about 16 mg, or from about 11.5 mg to about 24 mg, orfrom about 15 mg to about 32 mg of buprenorphine base or a an equimolaramount of a pharmaceutically acceptable salt thereof, or the TTScontains according to five different dosages from about 1 mg to about4.5 mg, or about 3 mg, or from about 4 mg to about 9 mg, or about 6 mg,or from about 8 mg to about 14 mg, or about 12 mg, or from about 15 mgto about 20 mg, or about 18 mg or from about 20 mg to about 28 mg, orabout 24 mg of buprenorphine base or a an equimolar amount of apharmaceutically acceptable salt thereof.

Pressure-Sensitive Adhesive

The Pressure-sensitive adhesives used for the present invention arepolymer-based pressure-sensitive adhesives. Such polymer-basedpressure-sensitive adhesives may e.g., be based on polysiloxanes orpolyisobutylenes. For the present invention polysiloxane basedpressure-sensitive adhesives are preferred. Such polysiloxanes adhesivesneed, unlike other organic pressures-sensitive adhesives, no additiveslike antioxidants, stabilizers, plasticizers, catalysts or otherpotentially extractable ingredients. These pressure-sensitive adhesivesprovide for suitable tack for quick bonding to various skin types,including wet skin, suitable adhesive and cohesive qualities, longlasting adhesion to the skin of up to 7 days, a high degree offlexibility, a permeability to moisture, and compatibility to manyactives and film-substrates. It is possible to provide them withsufficient amine resistance and therefore enhanced stability in thepresence of amines. Such pressure-sensitive adhesives are based on aresin-in-polymer concept wherein, by condensation reaction of silanolend blocked polydimethylsiloxane with a silica resin, a polysiloxane isprepared which for amine stability the residual silanol functionality isadditionally capped with trimethylsiloxy groups. The dimethiconolcontent contributes to the viscous component of the visco-elasticbehavior, and impacts the wetting and the spreadability properties ofthe adhesive. The resin acts as a tackifying and reinforcing agent, andparticipates in the elastic component. The correct balance betweendimethiconol and resin provides for the correct adhesive properties.

The adhesive strength of the polysiloxanes may be sufficient for thedesired skin contact. In certain embodiments of the invention aplasticizer or a tackifying agent is incorporated into the formulationto improve the adhesive characteristics of the pressure-sensitiveadhesive layer. It may be advantageous in an individual case to improvethe tack by adding small amounts of tackifiers such as polyterpenes,rosin derivatives, or silicone oils. In preferred embodiments, thetackifying agent is a silicone oil (e.g., 360 Medical Fluid, availablefrom Dow Corning Corporation, Midland, Mich.).

The pressure-sensitive adhesives are supplied and used in solvents likeheptane, ethyl acetate or other volatile silicone fluids. For thepresent invention heptane is preferred. The solids content is usuallybetween 60 and 80%.

The preferred pressure-sensitive adhesives based on polysiloxanes inaccordance with the invention are characterized by a solution viscosityat 25° C. and 60% solids content in heptane of more than about 150 mPas, or from about 200 mPa s to about 700 mPa s, in particular from about350 mPa s to about 600 mPa s, more preferred from about 480 mPa s toabout 550 mPa s, or most preferred of about 500 mPa s or alternativelyfrom about 400 mPa s to about 480 mPa s, or most preferred of about 450mPa s. Theses may also be characterized by a complex viscosity at 0.01rad/s at 30° C. of less than about 1×10⁹ Poise or from about 1×10⁵ toabout 9×10⁸ Poise, or more preferred from about 1×10 to about 1×10⁷Poise, or most preferred about 5×10⁶ Poise or alternatively morepreferred from about 2×10⁷ to about 9×10⁸ Poise, or most preferred about1×10⁸ Poise.

Suitable pressure-sensitive adhesives based on polysiloxanes may beobtained from Dow Corning® BIO-PSA Standard Silicone Adhesives.Preferred are the BIO-PSA 7 4301 and BIO-PSA 7 4201 Silicone Adhesives.According to certain embodiments BIO-PSA 7 4301 is preferred andaccording to certain other embodiments BIO-PSA 7 4201 is preferred.BIO-PSA 4201 has a solution viscosity at 25° C. and about 60% solidscontent in heptane of 450 mPa s and a complex viscosity at 0.01 rad/s at30° C. of 1×10° Poise. BIO-PSA 4301 has a solution viscosity at 25° C.and about 60% solids content in heptane of 500 mPa s and a complexviscosity at 0.01 rad/s at 30° C. of 1×10⁶ Poise.

The pressure-sensitive adhesive layer of the TTS of the invention mayfurther comprise in addition to the above mentioned ingredients a), b)and c), namely a polymer-based pressure-sensitive adhesive, thebuprenorphine and the carboxylic acid selected from the group of oleicacid, linoleic acid, linolenic acid and levulinic acid as describedherein, other various excipients or additives, for example from thegroup of solubilizers, fillers, tackifiers, substances which influencethe barrier properties of the stratum corneum in the sense of increasingthe active agent permeability, pH regulators, and preservatives.

Substances which influence the barrier properties of the stratum corneumin the sense of increasing the active agent permeability are known tothe skilled worker and the substance appropriate for the respectiveactive agents must—if necessary—be found by means of permeation studies.Some examples are polyhydric alcohols such as dipropylene glycol,propylene glycol, and polyethylene glycol; oils such as olive oil,squalene, and lanolin; fatty ethers such as cetyl ether and oleyl ether,fatty acid esters such as isopropyl myristate; urea and urea derivativessuch as allantoin; polar solvents such as dimethyldecylphosphoxide,methyloctylsulfoxide, dimethyllaurylamine, dodecylpyrrolidone,isosorbitol, dimethylacetonide, dimethylsulfoxide, decylmethylsulfoxide,and dimethylformamide; salicylic acid; amino acids; benzyl nicotinate;and higher molecular weight aliphatic surfactants such as lauryl sulfatesalts. Other agents include oleic and linoleic acids, ascorbic acid,panthenol, butylated hydroxytoluene, tocopherol, tocopheryl acetate,tocopheryl linoleate, propyl oleate, and isopropyl palmitate. The TTS ofthe invention may additionally comprise according to certain embodimentsin which the pressure-sensitive adhesive layer comprises a) thepolymer-based pressure-sensitive adhesive, b) the buprenorphine and c)levulinic acid or linolenic acid or mixtures of both as the carboxylicacid as described herein, oleic and linoleic acids as substancesinfluencing the barrier properties of the stratum corneum in the senseof increasing the active agent permeability.

Such substances as described in the previous paragraph may be includedin a TITS and may be present in an amount of about 1% to about 10% byweight. In a preferred embodiment of the present invention suchadditional substances are however not necessary. According to anembodiment of the invention the TTS does not comprise such additionalsubstances as mentioned in the previous paragraph.

In addition to the carboxylic acid selected from oleic acid, linoleicacid, linolenic acid, levulinic acid, the solubility of the drug can befurther altered by the optional addition of an agent that increases thesolubility of drug or inhibits drug crystallization in the transdermalcomposition, such as polyvinylpyrrolidone, vinylacetate/vinylpyrrolidone copolymer and cellulose derivatives.

Viscosity-increasing substances are preferably used in conjunction withan active agent solution. Suitable substances for increasing theviscosity of the active agent solution are, for example, cellulosederivatives such as ethylcellulose, hydroxylpropylcellulose and highmolecular mass polyacrylic acids and/or their salts and/or theirderivatives such as esters.

Fillers such as silica gels, titanium dioxide and zinc oxide may be usedin conjunction with the polymer in order to influence certain physicalparameters, such as cohesion and bond strength, in the desired way.

Buprenorphine-Containing Self-Adhesive Layer Structure

In accordance with the invention, the buprenorphine-containingself-adhesive layer structure comprises a buprenorphine-impermeablebacking layer, and a buprenorphine-containing pressure-sensitiveadhesive layer coated thereon. In a preferred embodiment, thebuprenorphine-containing self-adhesive layer structure consists of thesetwo elements.

The buprenorphine-containing pressure-sensitive adhesive layer may becoated at any dry weight, but is preferably coated at a dry weight ofmore than about 6 mg/cm² (about 60 g/m²), or of more than about 8 mg/cm²(about 80 g/m²), or ranging from about 6 mg/cm² (about 60 g/m²) to about14 mg/cm² (about 140 g/m²), or from about 8 mg/cm² (about 80 g/m²) toabout 14 mg/cm² (about 140 g/m²). Specifically, the dry weight is morethan about 10 mg/cm² (about 100 g/m²), or ranges from about 10 mg/cm²(about 100 g/m²) to about 13 mg/cm² (about 130 g/m²), or ranges fromabout 11.5 mg/cm² (about 115 g/m²) to about 12.5 mg/cm² (about 125g/m²), or is specifically about 12 mg/cm² (about 120 g/m²).

The dry buprenorphine-containing pressure-sensitive adhesive layerpreferably contains buprenorphine base, but may contain equimolaramounts of pharmaceutically acceptable salts. According to the inventionpreferably more than 5%, or more than about 6%, or more than about 7%,or more than about 8%, or more than about 9%, or from about 6% to about20%, or from about 7% to about 20%, or from about 8% to about 20%, orfrom about 9% to about 20%, or from about 6% to about 15%, or from about7% to about 15%, or from about 8 to about 15% or from about 9 to about15% buprenorphine base or equimolar amounts of pharmaceuticallyacceptable salts based on the total dry weight of the drybuprenorphine-containing pressure-sensitive adhesive layer are containedin the dry buprenorphine-containing pressure-sensitive adhesive layer.In a specific embodiment, about 10% buprenorphine base is contained inthe dry buprenorphine-containing pressure-sensitive adhesive layer.

Preferably, the TTS contains in the pressure-sensitive adhesive layermore than about 0.55 mg/cm², or more than about 0.6 mg/cm², or more thanabout 0.7 mg/cm², or more than about 0.8 mg/cm², or more than about 0.9mg/cm², or more than about 1 mg/cm², or more than about 1.1 mg/cm²,buprenorphine base, or from about 0.55 mg/cm² to about 2 mg/cm², or fromabout 0.6 mg/cm² to about 2 mg/cm², or from about 0.7 mg/cm² to about 2mg/cm², or from about 0.8 mg/cm² to about 2 mg/cm², or from about 0.9mg/cm² to about 2 mg/cm², or from about 1 mg/cm² to about 2 mg/cm², orfrom about 1.1 mg/cm² to about 2 mg/cm² buprenorphine base or containsabout 1.2 mg/cm² buprenorphine base. The TTS may also contain equimolaramounts of pharmaceutically acceptable salts.

In order to provide the desired delivery rate of buprenorphine, acarboxyclic acid is present. The carboxylic acid may be selected fromthe group consisting of oleic acid, linoleic acid, linolenic acid,levulinic acid and mixtures thereof, wherein levulinic acid ispreferred. The buprenorphine is in mixture with, e.g., dissolved in, thecarboxylic acid, e.g., the levulinic acid, and this mixture, e.g.,solution, is dispersed in the form of small deposits, e.g., droplets, inthe matrix layer. Buprenorphine, with its known physicochemicalproperties, namely its poor solubility, its comparatively high meltingpoint of 216° C., and its high molecular weight, tends readily towardscrystallization. For this reason, a solubilizer with at least one acidicgroup is used in order to prevent the buprenorphine from crystallizingduring the storage of the pharmaceutical form. Buprenorphine andlevulinic acid have an extremely low solubility in polysiloxanes. As aconsequence of this, it is possible to solubilize buprenorphine inlevulinic acid and to disperse this mixture in the form of smalldeposits in a matrix layer prepared on the basis of polysiloxanes asdescribed herein.

Levulinic acid is sparingly soluble in the organic solvents of theadhesives. Consequently, the liquid mixture of buprenorphine andlevulinic acid can be dispersed in the solution of the adhesive, withthe dispersion being retained following removal of the solvent. In amatrix layer of this kind, the solubility of the buprenorphine isdependent virtually only on the amount of the levulinic acid.

The amount of the dispersed mixture of buprenorphine, e.g.,buprenorphine base, and the carboxylic acid, e.g., levulinic acid, canbe up to about 40% by weight, it being preferred not to exceed about 25%or about 20% by weight and ranges from about 15% to about 25%, or fromabout 15% to about 20%, or from about 17% to about 20%. The deposit,e.g., droplet, size (diameter) itself ought preferably not to exceedabout 150 μm, or ranges from about 1 to about 150 μm, preferably fromabout 1 to about 50 μm, or from about 5 to about 50 μm, or from about 1to about 25 μm or from about 5 to about 25 μm. The preferred size isdependent, furthermore, on the thickness of the matrix layer.

Since the carboxylic acid, e.g., the levulinic acid, can likewise beabsorbed through the skin, the amount in the TTS becomes less as thetime of application elapses, and leads to a reduction of the solubilityof buprenorphine. As a result, the decrease in the thermodynamicactivity of buprenorphine due to depletion is compensated by the reduceddrug solubility in the buprenorphine/levulinic acid deposits.

According to the invention the dry buprenorphine-containingpressure-sensitive adhesive layer contains more than about 50%, or morethan about 6%, or more than about 7%, or more than about 8%, or morethan about 9%, or from about 6% to about 20%, or from about 7% to about20%, or from about 8 to about 20%, or from about 9 to about 20%, or fromabout 5% to about 15%, or from about 6% to about 15%, or from about 6%to about 9%, or from about 9% to about 15% carboxylic acid, e.g.,levulinic acid based on the total dry weight of the drybuprenorphine-containing pressure-sensitive adhesive layer. In aspecific embodiment the dry buprenorphine-containing pressure-sensitiveadhesive layer contains from about 6% to about 11% levulinic acid, orfrom about 6% to about 9% or from about 9% to about 15% levulinic acid,or about 7% levulinic acid or about 10% levulinic acid. According to aspecific embodiment the pressure-sensitive adhesive layer contains thesame %-amount of levulinic acid and buprenorphine base or equimolaramounts of pharmaceutically acceptable salts. According to anotherspecific embodiment, the pressure-sensitive adhesive layer contains less%-amount of levulinic acid than it contains %-amount of buprenorphinebase or equimolar amounts of pharmaceutically acceptable salts.

According to a specific embodiment, the pressure-sensitive adhesivelayer contains from more than 9% to about 15% buprenorphine base andfrom about 6% to about 9% levulinic acid or from more than 9% to about15% buprenorphine base and from about 9% to about 15% levulinic acidbased on the total dry weight.

According to a certain embodiment the pressure-sensitive adhesive layeris coated at a dry weight of from about 10 mg/cm² to about 14 mg/cm², orfrom about 11.5 mg/cm² to about 12.5 mg/cm² or is about 12 mg/cm², andthe dry pressure-sensitive adhesive layer contains from about 7% toabout 13% or from about 8% to about 12%, or from about 9% to about 11%or about 10% buprenorphine base and from about 6% to about 8/o, or about7% levulinic acid. In a specific embodiment the dry pressure-sensitiveadhesive layer has a dry weight of about 12 mg/cm² and contains about 7%levulinic acid and about 10% buprenorphine base.

According to a certain other embodiment, the pressure-sensitive adhesivelayer is coated at a dry weight of from about 10 mg/cm² to about 14mg/cm², or from about 11.5 mg/cm² to about 12.5 ing/cm², or is about 12mg/cm², and the dry pressure-sensitive adhesive layer contains fromabout 7% to about 13% or from about 8% to about 12%, or from about 9% toabout 11% or about 10% buprenorphine base and from about 8 to about 12%or about 10% levulinic acid. In a specific embodiment, the drypressure-sensitive adhesive layer has a dry weight of about 12 mg/cm²,and contains about 10% levulinic acid and about 10% buprenorphine base.

In accordance with the above, the TTS contains more than about 0.55mg/cm², or more than about 0.6 mg/cm², or more than about 0.7 mg/cm², ormore than about 0.8 mg/cm², or more than about 0.9 mg/cm², or more thanabout 1 mg/cm², or more than about 1.1 mg/cm² buprenorphine base or fromabout 0.6 mg/cm² to about 2 mg/cm², or from about 0.7 mg/cm² to about 2mg/cm², or from about 0.8 mg/cm² to about 2 mg/cm², or from about 0.9mg/cm² to about 2 mg/cm², or from about 1 mg/cm² to about 2 mg/cm², orfrom about 1.1 mg/cm² to about 2 mg/cm² buprenorphine base or containsabout 1.2 mg/cm² buprenorphine base or an equimolar amount of apharmaceutically acceptable salt thereof, buprenorphine base ispreferred. According to a specific embodiment, the pressure-sensitiveadhesive layer contains the same amounts of levulinic acid andbuprenorphine base. According to another specific embodiment, thepressure-sensitive adhesive layer contains less levulinic acid than itcontains buprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof.

According to a certain embodiment of the invention, thepressure-sensitive adhesive in the buprenorphine-containing layer and inthe active agent-free layer are different, and the adhesive in theactive agent-free layer is a pressure-sensitive adhesive based onpolyacrylates. According to certain other embodiments the adhesive inthe active agent-containing and the active agent-free layer are the sameand are an amine-resistant pressure-sensitive adhesive based onpolysiloxane wherein the polysiloxane is a product of the condensationreaction of silanol endblocked polydimethylsiloxane with a silica resinand the residual silanol functionality is capped with trimethylsiloxygroups and characterized by a solution viscosity at 25° C. and about 60%solids content in heptanes of about 500 mPa s or of about 450 mPa s, andthe buprenorphine-containing layer pressure-sensitive adhesive layer iscoated at a dry weight of about 12 mg/cm² and contains about 10%Buprenorphine base and about 10% levulinic acid.

According to certain embodiments, the area of release ranges from about1 cm² to about 38 cm², or the area of release is less than 25 cm², orless than 22 cm², or ranges from about 1.5 to about 25 cm², or fromabout 1.5 to about 22 cm², or from about 1.5 to about 20 cm², or isabout 3 cm² or about 6 cm², or about 10 cm², or about 15 cm² or about 20cm².

According to certain embodiments, the TTS contains from about 1 mg toabout 32 mg of buprenorphine base or an equimolar amount of apharmaceutically acceptable salt thereof, or from about 1 mg to about 28mg, or 2 mg to about 25 mg, or from about 2 mg to about 24 mg ofbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof. Considering five different increasing dosagestrengths, the TTS in specific cases preferably contains

-   -   a) from about 1 mg to about 4 mg, or from about 1 mg to about        4.5 mg, preferably from about 1 mg to about 3.5 mg, or from        about 2 mg to about 4 mg, more preferably from about 1 mg to        about 3 mg, or from about 2.5 mg to about 4 mg, or about 3 mg        buprenorphine base or an equimolar amount of a pharmaceutically        acceptable salt thereof, or    -   b) from about 3.5 mg to about 8 mg, or from about 4 mg to about        9 mg, preferably from about 3.5 mg to about 7 mg, or from about        5 mg to about 8 mg, more preferably from about 3.5 mg to about 6        mg, or from about 5 mg to about 7 mg, or about 6 mg        buprenorphine base or an equimolar amount of a pharmaceutically        acceptable salt thereof, or    -   c) from about 6.5 mg to about 16 mg, or from about 8 mg to about        14 mg, preferably from about 6.5 mg to about 14 mg, or from        about 10 mg to about 14 mg, more preferably from about 6.5 mg to        about 11 mg, or from about 11 mg to about 13 mg, or about 12 mg        buprenorphine base or an equimolar amount of a pharmaceutically        acceptable salt thereof, or    -   d) from about 11.5 mg to about 24 mg, or from about 15 mg to        about 20 mg, preferably from about 11.5 mg to about 21 mg, or        from about 16 mg to about 19 mg, more preferably from about 11.5        mg to about 14 mg, or from about 17 mg to about 19 mg, or about        18 mg buprenorphine base or an equimolar amount of a        pharmaceutically acceptable salt thereof, or    -   e) from about 15 mg to about 32 mg, or from about 20 mg to about        28 mg, preferably from about 15 mg to about 28 mg, or from about        21 mg to about 26 mg, more preferably from about 15 mg to about        24 mg, or from about 22 mg to about 25 mg, or about 24 mg of        buprenorphine base or an equimolar amount of a pharmaceutically        acceptable salt thereof.        Correspondingly the area of release ranges from about 1 cm² to        about 38 cm², or from 1.5 cm² to about 24 cm², or ranges from        1.5 cm² to about 22 cm², or ranges from 1.5 cm² to about 20 cm²        and with respect to the five specific preferred dosage        strengths a) to e)    -   a) ranges from about 1 cm² to about 4.8 cm², or from about 1.5        cm² to about 5.5 cm², preferably from about 1 cm² to about 4.5        cm², or from about 2 cm² to about 4 cm², more preferably from        about 2.5 cm² to about 4 cm², or from about 2 cm² to about 3        cm², or is about 2.5 cm², or    -   b) ranges from about 3 cm² to about 9.5 cm², or from about 3 cm²        to about 9 cm², preferably from about 3 cm² to about 9 cm², or        from about 4.5 cm² to about 7.5 cm², more preferably from about        5 cm² to about 8 cm², or from about 4.5 cm² to about 6 cm², or        is about 5 cm², or    -   c) ranges from about 6 cm² to about 19 cm², or from about 6 cm²        to about 14 cm², preferably from about 6 cm² to about 18 cm², or        from about 8 cm² to about 12 cm², more preferably from about 10        cm² to about 16 cm², or from about 9 cm² to about 11 cm², or is        about 10 cm², or    -   d) ranges from about 12 cm² to about 28.5 cm², or from about 13        cm² to about 17 cm², preferably from about 12 cm² to about 27        cm², or from about 13 cm² to about 16 cm², more preferably from        about 17 cm² to about 23 cm², or from about 14 cm² to about 16        cm², or is about 15 cm², or    -   e) ranges from about 16 cm² to about 38 cm², or from about 16        cm² to about 24 cm², preferably or from about 16 cm² to about 35        cm², or from about 17 cm² to about 22 cm², more preferably from        about 23.5 cm² to about 32 cm², or from about 18 cm² to about 21        cm², or is about 20 cm².        In such embodiments the dry pressure-sensitive adhesive layer        preferably comprises a pressure-sensitive adhesive based on        polysiloxanes and has preferably a dry weight of about 6 mg/cm²,        7.5 mg/cm², 8 mg/cm², 9 mg/cm², 10.5 mg/cm², or 12 mg/cm² and        contains 10% buprenorphine base.

According to certain preferred embodiments, the TTS contains withrespect to five dosage strengths a) to e) the following amounts ofbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides the following corresponding area ofrelease ranges:

a) about 1 cm² to about 1 cm² to about 2.5 cm² to a) about 4.8 cm² about4.5 cm² about 4 cm² about 1 mg X X x to about 4 mg about 1 mg X X X toabout 3.5 mg about 1 mg X X X to about 3 mg b) about 3 cm² to about 3cm² to about 5 cm² to b) about 9.5 cm² about 9 cm² about 8 cm² about 3.5mg X X X to about 8 mg about 3.5 mg X X X to about 7 mg about 3.5 mg X XX to about 6 mg c) about 6 cm² to about 6 cm² to about 10 cm² to c)about 19 cm² about 18 cm² about 16 cm² about 6.5 mg X X X to about 16 mgabout 6.5 mg X X X to about 14 mg about 6.5 mg X X X to about 11 mg d)about 12 cm² to about 12 cm² to about 17 cm² to d) about 28.5 cm² about27 cm² about 23 cm² about 11.5 mg X X X to about 24 mg about 11.5 mg X XX to about 21 mg about 11.5 mg X X X to about 14 mg e) about 16 cm² toabout 16 cm² to about 23.5 cm² e) about 38 cm² about 35 cm² to about 32cm² about 15 mg X X X to about 32 mg about 15 mg X X X to about 28 mgabout 15 mg X X X to about 24 mg

Set of Transdermal Therapeutic Systems

For the treatment of pain a patient needs to be titrated to theindividual dose of buprenorphine to adequately control the pain. Inorder to meet the individual requirements five different dosagestrengths are provided in accordance with the invention.

According to one aspect, the invention relates to a set of two (firstand second, or second and third, or third and fourth, or fourth andfifth TTS, or any other combination of two of the five different dosagestrengths), three (first to third, or second to fourth or third to fifthTS, or any other combination of three of the five different dosagestrengths), four (first to fourth or second to fifth TTS, or any othercombination of four of the five different dosage strengths) or five(first to fifth TTS) different transdermal therapeutic systems inaccordance with the invention, wherein: the first transdermaltherapeutic system provides a size of said buprenorphine-containingpressure-sensitive adhesive layer providing the area of release rangingfrom about 1 cm² to about 4.8 cm², or from about 1.5 cm² to about 5.5cm² and contains an amount of said buprenorphine from about 1 mg toabout 4 mg, or from about 1 mg to about 4.5 mg buprenorphine base or anequimolar amount of a pharmaceutically acceptable salt thereof; and

the second transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 3 cm² to about 9.5 cm², or from about3 cm² to about 9 cm² and contains an amount of said buprenorphine fromabout 3.5 mg to about 8 mg, or from about 4 mg to about 9 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof, andthe third transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 6 cm² to about 19 cm², or from about6 cm² to about 14 cm² and contains an amount of said buprenorphine fromabout 6.5 mg to about 16 mg, or from about 8 mg to about 14 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof; andthe fourth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 12 cm² to about 28.5 cm², or fromabout 13 cm² to about 17 cm² and contains an amount of saidbuprenorphine from about 11.5 mg to about 24 mg, or from about 15 mg toabout 20 mg buprenorphine base or an equimolar amount of apharmaceutically acceptable salt thereof; andthe fifth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 16 cm² to about 38 cm², or from about16 cm² to about 24 cm² and contains an amount of said buprenorphine fromabout 15 mg to about 32 mg, or from about 20 mg to about 28 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof.

The invention relates also to set of transdermal therapeutic systems,wherein:

the first transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 1 cm² to about 4.5 cm², or from about2 cm² to about 4 cm² and contains an amount of said buprenorphine fromabout 1 mg to about 3.5 mg, or from about 2 mg to about 4 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof; andthe second transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 3 cm² to about 9 cm², or from about4.5 cm² to about 7.5 cm² and contains an amount of said buprenorphinefrom about 3.5 mg to about 7 mg, or from about 5 mg to about 8 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof; andthe third transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 6 cm² to about 18 cm², or from about8 cm² to about 12 cm² and contains an amount of said buprenorphine fromabout 6.5 mg to about 14 mg, or from about 10 mg to about 14 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof; andthe fourth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 12 cm² to about 27 cm², or from about13 cm² to about 16 cm² and contains an amount of said buprenorphine fromabout 11.5 mg to about 21 mg, or from about 16 mg to about 19 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof; andthe fifth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 16 cm² to about 35 cm², or from about17 cm² to about 22 cm² and contains an amount of said buprenorphine fromabout 15 mg to about 28 mg, or from about 21 mg to about 26 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof.

The invention relates also to set of different transdermal therapeutic,wherein:

the first transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 2.5 cm² to about 4 cm², or from about2 cm² to about 3 cm² and contains an amount of said buprenorphine fromabout 1 mg to about 3 mg, or from about 2.5 mg to about 4 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof; andthe second transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 5 cm² to about 8 cm², or from about4.5 cm² to about 6 cm² and contains an amount of said buprenorphine fromabout 3.5 mg to about 6 m& or from about 5 mg to about 7 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof; andthe third transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 10 cm² to about 16 cm², or from about9 cm² to about 11 cm² and contains an amount of said buprenorphine fromabout 6.5 mg to about 11 mg, or from about 11 mg to about 13 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof; andthe fourth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 17 cm² to about 23 cm², or from about14 cm² to about 16 cm² and contains an amount of said buprenorphine fromabout 11.5 mg to about 14 mg, or from about 17 mg to about 19 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof; andthe fifth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 23.5 cm² to about 32 cm², or fromabout 18 cm² to about 21 cm² and contains an amount of saidbuprenorphine from about 15 mg to about 24 mg, or from about 22 mg toabout 25 mg buprenorphine base or an equimolar amount of apharmaceutically acceptable salt thereof.

In a further aspect of the invention a transdermal therapeutic systemselected from a set of transdermal therapeutic systems as described inthe previous paragraphs is provided wherein buprenorphine is present inthe form of buprenorphine base and wherein

the first transdermal therapeutic system when tested in a comparativeclinical study is bioequivalent to a reference product having an area ofrelease of about 6.25 cm² and providing a nominal mean release rate ofabout 5 μg/hr over about 168 hours of administration,the second transdermal therapeutic system when tested in a comparativeclinical study is bioequivalent to a reference product having an area ofrelease of about 12.5 cm² and providing a nominal mean release rate ofabout 10 μg/hr over about 168 hours of administration,the third transdermal therapeutic system when tested in a comparativeclinical study is bioequivalent to a reference product having an area ofrelease of about 25 cm² and providing a nominal mean release rate ofabout 20 μg/hr over about 168 hours of administration,the fourth transdermal therapeutic system when tested in a comparativeclinical study is bioequivalent to a reference product having an area ofrelease of about 37.5 cm² and providing a nominal mean release rate ofabout 30 μg/hr over about 168 hours of administration,the fifth transdermal therapeutic system when tested in a comparativeclinical study is bioequivalent to a reference product having an area ofrelease of about 50 cm² and providing a nominal mean release rate ofabout 40 μg/hr over about 168 hours of administration,wherein the reference product is prepared by the following steps:

-   -   1. homogenizing of 1,139 g of a 47.83% polyacrylate solution of        a self-crosslinked acrylate copolymer of 2-ethylhexyl acrylate,        vinyl acetate, acrylic acid (solvent: ethyl        acetate:heptanes:isopropanol:toluene:acetylacetonate in the        ratio of 37:26:26:4:1), 100 g of levulinic acid, 150 g of oleyl        oleate, 100 g of polyvinylpyrrolidone, 150 g of ethanol, 200 g        of ethyl acetate, and 100 g of buprenorphine base to provide a        mixture;    -   2. stirring the mixture of step 1 for about 2 hours and        controlling the dissolution of all solids visually whereas        controlling the evaporation loss by reweighing and replenishing        the possible solvent loss by ethyl acetate;    -   3. subsequently applying the mixture on a transparent polyester        film in such a manner that the mass per unit area of the dry        adhesive layer amounts to about 80 g/m² wherein the polyester        film is rendered removable by means of siliconization and serves        as protective layer,    -   4. removing the solvents of the mixture applied on a transparent        polyester film in step 3 by drying with heated air which is led        over a moist lane resulting in evaporation of the solvents, but        also in melting of the levulinic acid and covering the adhesive        film with a polyester foil;    -   5. punching the area of release of 6.25 cm², 12.5 cm², 25 cm²,        37.5 cm² and 50 cm², respectively, by means of suitable cutting        tools and removing the edges left between the individual        systems.

According to one aspect, the invention relates to a transdermaltherapeutic system described as first transdermal therapeutic system inthe previous paragraphs wherein buprenorphine is present in the form ofbuprenorphine base and which is when tested in a comparative clinicalstudy bioequivalent to the commercial product BuTrans®, also known asNorspan®, having an area of release of 6.25 cm².

According to one aspect, the invention relates to a transdermaltherapeutic system described as second transdermal therapeutic system inthe previous paragraphs wherein buprenorphine is present in the form ofbuprenorphine base and which is when tested in a comparative clinicalstudy bioequivalent to the commercial product BuTrans®, also known asNorspan®, having an area of release of 12.5 cm².

According to one aspect, the invention relates to a transdermaltherapeutic system described as third transdermal therapeutic system inthe previous paragraphs wherein buprenorphine is present in the form ofbuprenorphine base and which is when tested in a comparative clinicalstudy bioequivalent to the commercial product BuTrans®, also known asNorspan®, having an area of release of 25 cm².

According to one aspect, the invention relates to a transdermaltherapeutic system comprising buprenorphine for the transdermaladministration of buprenorphine selected from:

a first transdermal therapeutic system providing a size of the area ofrelease ranging from about 1 cm² to about 4.8 cm² and containing anamount of said buprenorphine from 1 mg to about 4 mg buprenorphine baseor an equimolar amount of a pharmaceutically acceptable salt thereof andproviding a nominal mean release rate of about 5 μg/hr and/or providinga mean AUCt of more than 7,000 pg·hr/ml, preferably more than 8,000pg·hr/ml, or of from more than 7,000 pg·hr/ml to about 16,000 pg·hr/ml,or of from more than 8,000 pg·hr/ml to about 16,000 pg·hr/ml over about168 hours of administration after a single-dose administration to asubject population;a second transdermal therapeutic system providing a size of the area ofrelease ranging from about 3 cm² to about 9.5 cm² and containing anamount of said buprenorphine from about 3.5 mg to about 8 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a nominal mean release rate ofabout 10 μg/hr and/or providing a mean AUCt of more than 14,000pg·hr/ml, preferably of more than 16,000 pg·hr/ml, or of from more than14,000 pg·hr/ml to about 32,000 pg·hr/ml, or of from more than 16,000pg·hr/ml to about 32,000 pg·hr/ml over about 168 hours of administrationafter a single-dose administration to a subject population; anda third transdermal therapeutic system providing a size of the area ofrelease ranging from about 6 cm² to about 19 cm² and containing anamount of said buprenorphine from about 6.5 mg to about 16 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a nominal mean release rate ofabout 20 μg/hr and/or providing a mean AUCt of more than 28,000pg·hr/ml, preferably of more than 32,000 pg·hr/ml, or of from more than28,000 pg·hr/ml to about 64,000 pg·hr/ml, or of from more than 32,000pg·hr/ml to about 64,000 pg·hr/ml over about 168 hours of administrationafter a single-dose administration to a subject population; anda fourth transdermal therapeutic system providing a size of the area ofrelease ranging from about 12 cm² to about 28.5 cm² and containing anamount of said buprenorphine from about 11.5 mg to about 24 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a nominal mean release rate ofabout 30 μg/hr and/or providing a mean AUCt of more than 42,000pg·hr/ml, preferably of more than 48,000 pg·hr/ml, or of from more than42,000 pg·hr/ml to about 96,000 pg·hr/ml, or of from more than 48,000pg·hr/ml to about 96,000 pg·hr/ml over about 168 hours of administrationafter a single-dose administration to a subject population; anda fifth transdermal therapeutic system providing a size of the area ofrelease ranging from about 16 cm² to about 38 cm² and containing anamount of said buprenorphine from about 15 mg to about 32 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a nominal mean release rate ofabout 40 μg/hr and/or providing a mean AUCt of more than 62,000pg·hr/ml, preferably of more than 64,000 pg·hr/ml, or of from more than62,000 pg·hr/ml to about 128,000 pg·hr/ml, or of from more than 64,000pg·hr/ml to about 128,000 pg·hr/ml over about 168 hours ofadministration after a single-dose administration to a subjectpopulation.

According to one aspect, the invention relates to a transdermaltherapeutic system comprising buprenorphine for the transdermaladministration of buprenorphine selected from:

a first transdermal therapeutic system providing a size of the area ofrelease ranging from about 1 cm² to about 4.5 cm² and containing anamount of said buprenorphine from 1 mg to about 3.5 mg buprenorphinebase or an equimolar amount of a pharmaceutically acceptable saltthereof and providing a nominal mean release rate of about 5 μg/hrand/or providing a mean AUCt of more than 7,000 pg·hr/ml, preferablymore than 8,000 pg·hr/ml, or of from more than 7,000 pg·hr/ml to about16,000 pg·hr/ml, or of from more than 8,000 pg·hr/ml to about 16,000pg·hr/ml over about 168 hours of administration after a single-doseadministration to a subject population;a second transdermal therapeutic system providing a size of the area ofrelease ranging from about 3 cm² to about 9 cm² and containing an amountof said buprenorphine from about 3.5 mg to about 7 mg buprenorphine baseor an equimolar amount of a pharmaceutically acceptable salt thereof andproviding a nominal mean release rate of about 10 μg/hr and/or providinga mean AUCt of more than 14,000 pg·hr/ml, preferably of more than 16,000pg·hr/ml, or of from more than 14,000 pg·hr/ml to about 32,000 pg·hr/ml,or of from more than 16,000 pg·hr/ml to about 32,000 pg·hr/ml over about168 hours of administration after a single-dose administration to asubject population; anda third transdermal therapeutic system providing a size of the area ofrelease ranging from about 6 cm² to about 18 cm² and containing anamount of said buprenorphine from about 6.5 mg to about 14 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a nominal mean release rate ofabout 20 μg/hr and/or providing a mean AUCt of more than 28,000pg·hr/ml, preferably of more than 32,000 pg·hr/ml, or of from more than28,000 pg·hr/ml to about 64,000 pg·hr/ml, or of from more than 32,000pg·hr/ml to about 64,000 pg·hr/ml over about 168 hours of administrationafter a single-dose administration to a subject population; anda fourth transdermal therapeutic system providing a size of the area ofrelease ranging from about 12 cm² to about 27 cm² and containing anamount of said buprenorphine from about 11.5 mg to about 21 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a nominal mean release rate ofabout 30 μg/hr and/or providing a mean AUCt of more than 42,000pg·hr/ml, preferably of more than 48,000 pg·hr/ml, or of from more than42,000 pg·hr/ml to about 96,000 pg·hr/ml, or of from more than 48,000pg·hr/ml to about 96,000 pg·hr/ml over about 168 hours of administrationafter a single-dose administration to a subject population; anda fifth transdermal therapeutic system providing a size of the area ofrelease ranging from about 16 cm² to about 35 cm² and containing anamount of said buprenorphine from about 15 mg to about 28 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a nominal mean release rate ofabout 40 μg/hr and/or providing a mean AUCt of more than 62,000pg·hr/ml, preferably of more than 64,000 pg·hr/ml, or of from more than62,000 pg·hr/ml to about 128,000 pg·hr/ml, or of from more than 64,000pg·hr/ml to about 128,000 pg·hr/ml over about 168 hours ofadministration after a single-dose administration to a subjectpopulation.

According to one aspect, the invention relates a transdermal therapeuticsystem comprising buprenorphine for the transdermal administration ofbuprenorphine selected from:

a first transdermal therapeutic system providing a size of the area ofrelease ranging from about 2.5 cm² to about 4 cm² and containing anamount of said buprenorphine from 1 mg to about 3 mg buprenorphine baseor an equimolar amount of a pharmaceutically acceptable salt thereof andproviding a nominal mean release rate of about 5 μg/hr and/or providinga mean AUCt of more than 7,000 pg·hr/ml, preferably more than 8,000pg·hr/ml, or of from more than 7,000 pg·hr/ml to about 16,000 pg·hr/ml,or of from more than 8,000 pg·hr/ml to about 16,000 pg·hr/ml over about168 hours of administration after a single-dose administration to asubject population;a second transdermal therapeutic system providing a size of the area ofrelease ranging from about 5 cm² to about 8 cm² and containing an amountof said buprenorphine from about 3.5 mg to about 6 mg buprenorphine baseor an equimolar amount of a pharmaceutically acceptable salt thereof andproviding a nominal mean release rate of about 10 μg/hr and/or providinga mean AUCt of more than 14,000 pg·hr/ml, preferably of more than 16,000pg·hr/ml, or of from more than 14,000 pg·hr/ml to about 32,000 pg·hr/ml,or of from more than 16,000 pg·hr/ml to about 32,000 pg·hr/ml over about168 hours of administration after a single-dose administration to asubject population; anda third transdermal therapeutic system providing a size of the area ofrelease ranging from about 10 cm² to about 16 cm² and containing anamount of said buprenorphine from about 6.5 mg to about 11 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a nominal mean release rate ofabout 20 μg/hr and/or providing a mean AUCt of more than 28,000pg·hr/ml, preferably of more than 32,000 pg·hr/ml, or of from more than28,000 pg·hr/ml to about 64,000 pg·hr/ml, or of from more than 32,000pg·hr/ml to about 64,000 pg·hr/ml over about 168 hours of administrationafter a single-dose administration to a subject population; anda fourth transdermal therapeutic system providing a size of the area ofrelease ranging from about 17 cm² to about 23 cm² and containing anamount of said buprenorphine from about 11.5 mg to about 14 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a nominal mean release rate ofabout 30 μg/hr and/or providing a mean AUCt of more than 42,000pg·hr/ml, preferably of more than 48,000 pg·hr/ml, or of from more than42,000 pg·hr/ml to about 96,000 pg·hr/ml, or of from more than 48,000pg·hr/ml to about 96,000 pg·hr/ml over about 168 hours of administrationafter a single-dose administration to a subject population; anda fifth transdermal therapeutic system providing a size of the area ofrelease ranging from about 23.5 cm² to about 32 cm² and containing anamount of said buprenorphine from about 15 mg to about 24 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a nominal mean release rate ofabout 40 μg/hr and/or providing a mean AUCt of more than 62,000pg·hr/ml, preferably of more than 64,000 pg·hr/ml, or of from more than62,000 pg·hr/ml to about 128,000 pg·hr/ml, or of from more than 64,000pg·hr/ml to about 128,000 pg·hr/ml over about 168 hours ofadministration after a single-dose administration to a subjectpopulation.

Release Characteristic

In accordance with the invention, the TTS is further characterized bythe skin permeation rate determined by in vitro experiments carried outwith the Franz diffusion cell (e.g., a 9 ml Franz diffusion cell), usinghuman split thickness skin. Skin from cosmetic surgeries (female breast,date of birth 1989) can be used. A dermatone is used to prepare skin toa thickness of 800 μm, with an intact epidermis, in accordance with theOECD Guideline (adopted Apr. 13, 2004). Due to the prolonged test (168hours) 800 μm skin is used instead of the recommended 200 to 400 μmskin. The receptor medium used is a phosphate buffer solution pH 5.5with 0.1% saline azide as antibacteriological agent is used at atemperature of 32±1°. Example formulations with an area of 1.163 cm² arepunched from laminates, and in the present examples are each testedagainst 1.163 cm² samples of the commercial product Norspan®. Theconcentrations of buprenorphine in the acceptor medium of the Franz cellare measured.

The ITS according to the invention provides a mean cumulative skinpermeation rate of more than about 1.3 μg/cm²-hr, or more than about 1.5μg/cm²-hr or more than about 1.7 μg/cm²-hr over a 168 hours test, or ofmore than about 2 μg/cm²-hr over a 168 hours test, or of more than about2.5 μg/cm²-hr over a 168 hours test, or of more than 2.7 μg/cm²-hr overa 168 hours test, or of more than about 3 μg/cm²-hr over a 168 hourstest, or from about 1.3 μg/cm²-hr to about 4 μg/cm²-hr, or from about1.7 μg/cm²-hr to about 4 μg/cm²-hr, or from about 2 μg/cm²-hr to about 4μg/cm²-hr, or from about 2.5 μg/cm²-hr to about 4 μg/cm²-hr, or fromabout 2.7 μg/cm²-hr to about 4 μg/cm²-hr, or from about 3 μg/cm²-hr toabout 4 μg/cm²-hr, over a 168 hours test. The commercial productNorspan® provides a mean cumulative skin permeation rate of about 1μg/cm²-hr over a 168 hours test in said test.

According to certain embodiments, the TTS provides a cumulative releaseas measured in a Franz diffusion cell as mentioned above of about 220μg/cm² to about 640 μg/cm² over a time period of 168 hours, or of about400 μg/cm² to about 640 μg/cm², or of about 450 μg/cm² to about 640μg/cm², or of about 500 μg/cm² to about 640 μg/cm², or of about 600μg/cm² to about 640 μg/cm² over a time period of 168 hours. Thecommercial product Norspan® provides a cumulative release of about175.29 μg/cm² in said test. As can be seen from FIG. 2, comparable skinpermeation rates are measured using the 25 cm² Norspan® TTS including 20mg buprenorphine base and TTS examples 1 to 4 in accordance with theinvention with an area of 10 cm² and including 12 mg buprenorphine base.This corresponds to about a 60% size reduction and a reduction of about40% in the amount of used buprenorphine base.

According to certain embodiments, the TTS provides a non-cumulative skinpermeation rate of buprenorphine base as measured in a Franz diffusioncell of

2 μg/cm² to 10 μg/cm² in the first 8 hours,20 μg/cm² to 80 μg/cm² from hour 8 to hour 24,20 μg/cm² to 80 μg/cm² from hour 24 to hour 32,30 μg/cm² to 120 μg/cm² from hour 32 to hour 48,40 μg/cm² to 150 μg/cm² from hour 48 to hour 72,100 μg/cm² to 300 μg/cm² from hour 72 to hour 144, and30 μg/cm² to 100 μg/cm² from hour 144 to hour 168.

According to certain embodiments, the TTS provides a non-cumulative skinpermeation rate of buprenorphine base as measured in a Franz diffusioncell of

2 μg/cm² to 6 μg/cm² in the first 8 hours,25 μg/cm² to 60 μg/cm² from hour 8 to hour 24,25 μg/cm² to 60 μg/cm² from hour 24 to hour 32,40 μg/cm² to 100 μg/cm² from hour 32 to hour 48,50 μg/cm² to 140 μg/cm² from hour 48 to hour 72,100 μg/cm² to 280 μg/cm² from hour 72 to hour 144, and30 μg/cm² to 100 μg/cm² from hour 144 to hour 168.

According to certain embodiments, the TTS provides a non-cumulative skinpermeation rate of buprenorphine base as measured in a Franz diffusioncell of

3 μg/cm² to 6 μg/cm² in the first 8 hours,30 μg/cm² to 50 μg/cm² from hour 8 to hour 24,30 μg/cm² to 50 μg/cm² from hour 24 to hour 32.60 μg/cm² to 90 μg/cm² from hour 32 to hour 48,100 μg/cm² to 130 μg/cm² from hour 48 to hour 72,200 μg/cm² to 280 μg/cm² from hour 72 to hour 144, and60 μg/cm² to 100 μg/cm² from hour 144 to hour 168.

The commercial product Norspan® provides a non-cumulative skinpermeation rate of buprenorphine base as measured in a Franz diffusioncell in the same setting of

3.19 μg/cm² in the first 8 hours,22.40 μg/cm² from hour 8 to hour 24,13.83 μg/cm² from hour 24 to hour 32,26.17 μg/cm² from hour 32 to hour 48,32.43 μg/cm² from hour 48 to hour 72,60.10 μg/cm² from hour 72 to hour 144, and17.17 μg/cm² from hour 144 to hour 168.

Method of Treatment/Medical Use

According to one aspect, the transdermal therapeutic system inaccordance with the invention and as described above in detail is foruse in a method of treating pain. The Method comprises in particular theapplication of the TTS for about 168 hours (corresponding to 7 days orone week) on the skin of a patient. According to other methods inaccordance with the invention the TTS can be applied for more than about96 hours corresponding to more than 4 days, or about 120 hourscorresponding to 5 days and about 144 hours corresponding to 6 days. Theapplication for about 168 hours is preferred.

According to one aspect, the invention relates to a method of treatmentwherein a set of five different transdermal therapeutic systemscorresponding to different dosage strengths and corresponding differentnominal mean release rates and/or mean release rates over about 168hours of administration is used, wherein:

the first transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 1.5 cm² to about 5.5 cm² and containsan amount of said buprenorphine from about 1 mg to about 4.5 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine ranging from about 2.5 to about 7.5 μg/hr or from about 4to about 6 gag/hr, and/or provides a nominal mean release rate ofbuprenorphine of about 5 μg/hr over about 168 hours of administration;andthe second transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 3 cm² to about 9 cm² and contains anamount of said buprenorphine from about 4 mg to about 9 mg buprenorphinebase or an equimolar amount of a pharmaceutically acceptable saltthereof and provides a mean release rate of buprenorphine ranging fromabout 8 to about 12 μg/hr or from about 9 to about 11 μg/hr, and/orprovides a nominal mean release rate of buprenorphine of about 10 μg/hrover about 168 hours of administration; andthe third transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 6 cm² to about 14 cm² and contains anamount of said buprenorphine from about 8 mg to about 14 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine ranging from about 15 to about 25 μg/hr or from about 17to about 22 μg/hr, and/or provides a nominal mean release rate ofbuprenorphine of about 20 μg/hr over about 168 hours of administration;andthe fourth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 13 cm² to about 17 cm² and containsan amount of said buprenorphine from about 15 mg to about 20 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine ranging from about 26 to about 35 μg/hr or from about 27to about 32 μg/hr, and/or provides a nominal mean release rate ofbuprenorphine of about 30 μg/hr over about 168 hours of administration;andthe fifth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 16 cm² to about 24 cm² and containsan amount of said buprenorphine from about 20 mg to about 28 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine ranging from about 36 to about 45 μg/hr or from about 38to about 42 μg/hr, and/or provides a nominal mean release rate ofbuprenorphine of about 40 μg/hr over about 168 hours of administration.

The invention relates also to set of transdermal therapeutic systems,wherein:

the first transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 2 cm² to about 4 cm² and contains anamount of said buprenorphine from about 2 mg to about 4 mg buprenorphinebase or an equimolar amount of a pharmaceutically acceptable saltthereof and provides a mean release rate of buprenorphine ranging fromabout 2.5 to about 7.5 μg/hr or from about 4 to about 6 μg/hr, and/orprovides a nominal mean release rate of buprenorphine of about 5 μg/hrover about 168 hours of administration; andthe second transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 4.5 cm² to about 7.5 cm² and containsan amount of said buprenorphine from about 5 mg to about 8 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine ranging from about 8 to about 12 μg/hr or from about 9 toabout 11 μg/hr, and/or provides a nominal mean release rate ofbuprenorphine of about 10 μg/hr over about 168 hours of administration;andthe third transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 8 cm² to about 12 cm² and contains anamount of said buprenorphine from about 10 mg to about 14 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine ranging from about 15 to about 25 μg/hr or from about 17to about 22 μg/hr, and/or provides a nominal mean release rate ofbuprenorphine of about 20 μg/hr over about 168 hours of administration;andthe fourth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 13 cm² to about 16 cm² and containsan amount of said buprenorphine from about 16 mg to about 19 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine ranging from about 26 to about 35 μg/hr or from about 27to about 32 μg/hr, and/or provides a nominal mean release rate ofbuprenorphine of about 30 μg/hr over about 168 hours of administration;andthe fifth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 17 cm² to about 22 cm² and containsan amount of said buprenorphine from about 21 mg to about 26 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine ranging from about 36 to about 45 μg/hr or from about 38to about 42 μg/hr, and/or provides a nominal mean release rate ofbuprenorphine of about 40 μg/hr over about 168 hours of administration.

The invention relates also to set of different transdermal therapeutic,wherein:

the first transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 2 cm² to about 3 cm² and contains anamount of said buprenorphine from about 2.5 mg to about 4 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine ranging from about 2.5 to about 7.5 μg/hr or from about 4to about 6 μg/hr, and/or provides a nominal mean release rate ofbuprenorphine of about 5 μg/hr over about 168 hours of administration;andthe second transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 4.5 cm² to about 6 cm² and containsan amount of said buprenorphine from about 5 mg to about 7 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine ranging from about 8 to about 12 μg/hr or from about 9 toabout 11 μg/hr, and/or provides a nominal mean release rate ofbuprenorphine of about 10 μg/hr over about 168 hours of administration;andthe third transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 9 cm² to about 11 cm² and contains anamount of said buprenorphine from about 11 mg to about 13 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine ranging from about 15 to about 25 μg/hr or from about 17to about 22 μg/hr, and/or provides a nominal mean release rate ofbuprenorphine of about 20 μg/rh over about 168 hours of administration;andthe fourth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 14 cm² to about 16 cm² and containsan amount of said buprenorphine from about 17 mg to about 19 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine ranging from about 26 to about 35 μg/hr or from about 27to about 32 μg/hr, or about 30 rag/hr over about 168 hours ofadministration; and the fifth transdermal therapeutic system provides asize of said buprenorphine-containing pressure-sensitive adhesive layerproviding the area of release ranging from about 18 cm² to about 21 cm²and contains an amount of said buprenorphine from about 22 mg to about25 mg buprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine ranging from about 36 to about 45 μg/hr or from about 38to about 42 μg/hr, and/or provides a nominal mean release rate ofbuprenorphine of about 40 μg/hr over about 168 hours of administration.

According to one aspect, the invention relates to a method of treatingpain in a patient wherein said patient is treated with one appropriatelyselected TTS from a set of two (first and second, or second and third,or third and fourth, or fourth and fifth TTS, or any other combinationof two of the five different dosage strengths), three (first to third,or second to fourth or third to fifth TTS, or any other combination ofthree of the five different dosage strengths), four (first to fourth orsecond to fifth TTS, or any other combination of four of the fivedifferent dosage strengths) or five (first to fifth TTS) differenttransdermal therapeutic systems corresponding to different dosagestrengths and corresponding different nominal mean release rates and/ormean release rates over about 168 hours of administration is used,wherein:

the first transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 1 cm² to about 4.8 cm² and containsan amount of said buprenorphine from about 1 mg to about 4 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine of at least about 2 μg/hr, or of from about 2.5 to about7.5 μg/hr or from about 4 to about 6 μg/hr, and/or provides a nominalmean release rate of buprenorphine of about 5 μg/hr over about 168 hoursof administration; andthe second transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 3 cm² to about 9.5 cm² and containsan amount of said buprenorphine from about 3.5 mg to about 8 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine of at least about 6 μg/hr, or of from about 8 to about 12μg/hr or from about 9 to about 11 μg/hr, and/or provides a nominal meanrelease rate of buprenorphine of about 10 μg/hr over about 168 hours ofadministration; andthe third transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 6 cm² to about 19 cm² and contains anamount of said buprenorphine from about 6.5 mg to about 16 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine of at least about 11 μg/hr, or of from about 15 to about25 μg/hr or from about 17 to about 22 μg/hr, and/or provides a nominalmean release rate of buprenorphine of about 20 μg/hr over about 168hours of administration; andthe fourth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 12 cm² to about 28.5 cm² and containsan amount of said buprenorphine from about 11.5 mg to about 24 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine of at least about 21 μg/hr, or of from about 26 to about35 μg/hr or from about 27 to about 32 μg/hr, and/or provides a nominalmean release rate of buprenorphine of about 30 μg/hr over about 168hours of administration; andthe fifth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 16 cm² to about 38 cm² and containsan amount of said buprenorphine from about 15 mg to about 32 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine of at least about 31 μg/hr, or of from about 36 to about45 gig/hr or from about 38 to about 42 μg/hr, and/or provides a nominalmean release rate of buprenorphine of about 40 μg/hr over about 168hours of administration.

The invention relates also to set of transdermal therapeutic systems,wherein:

the first transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 1 cm² to about 4.5 cm² and containsan amount of said buprenorphine from about 1 mg to about 3.5 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine of at least about 2 μg/hr, or of from about 2.5 to about7.5 μg/hr or from about 4 to about 6 μg/hr, and/or provides a nominalmean release rate of buprenorphine of about 5 μg/hr over about 168 hoursof administration; andthe second transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 3 cm² to about 9 cm² and contains anamount of said buprenorphine from about 3.5 mg to about 7 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine of at least about 6 μg/hr, or of from about 8 to about 12μg/hr or from about 9 to about 1 μg/hr, and/or provides a nominal meanrelease rate of buprenorphine of about 10 μg/hr over about 168 hours ofadministration; andthe third transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 6 cm² to about 18 cm² and contains anamount of said buprenorphine from about 6.5 mg to about 14 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine of at least about 11 μg/hr, or of from about 15 to about25 μg/hr or from about 17 to about 22 μg/hr, and/or provides a nominalmean release rate of buprenorphine of about 20 μg/hr over about 168hours of administration; andthe fourth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 12 cm² to about 27 cm² and containsan amount of said buprenorphine from about 11.5 mg to about 21 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine of at least about 21 μg/hr, or of from about 26 to about35 μg/hr or from about 27 to about 32 μg/hr, and/or provides a nominalmean release rate of buprenorphine of about 30 μg/hr over about 168hours of administration; andthe fifth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 16 cm² to about 35 cm² and containsan amount of said buprenorphine from about 15 mg to about 28 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine of at least about 31 μg/hr, or of from about 36 to about45 μg/hr or from about 38 to about 42 μg/hr, and/or provides a nominalmean release rate of buprenorphine of about 40 μg/hr over about 168hours of administration.

The invention relates also to set of different transdermal therapeutic,wherein:

the first transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 2.5 cm² to about 4 cm² and containsan amount of said buprenorphine from about 1 mg to about 3 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine of at least about 2 μg/hr, or of from about 2.5 to about7.5 rμg/hr or from about 4 to about 6 μg/hr, and/or provides a nominalmean release rate of buprenorphine of about 5 μg/hr over about 168 hoursof administration; andthe second transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 5 cm² to about 8 cm² and contains anamount of said buprenorphine from about 3.5 mg to about 6 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine of at least about 6 μg/hr, or of from about 8 to about 12μg/hr or from about 9 to about 11 μg/hr, and/or provides a nominal meanrelease rate of buprenorphine of about 10 μg/hr over about 168 hours ofadministration; and the third transdermal therapeutic system provides asize of said buprenorphine-containing pressure-sensitive adhesive layerproviding the area of release ranging from about 10 cm² to about 16 cm²and contains an amount of said buprenorphine from about 6.5 mg to about11 mg buprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine of at least about 11 μg/hr, or of from about 15 to about25 μg/hr or from about 17 to about 22 μg/hr, and/or provides a nominalmean release rate of buprenorphine of about 20 μg/hr over about 168hours of administration; andthe fourth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 17 cm² to about 23 cm² and containsan amount of said buprenorphine from about 11.5 mg to about 14 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine of at least about 21 μg/hr, or of from about 26 to about35 μg/hr or from about 27 to about 32 μg/hr, and/or provides a nominalmean release rate of buprenorphine of about 30 μg/hr over about 168hours of administration; andthe fifth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 23.5 cm² to about 32 cm² and containsan amount of said buprenorphine from about 15 mg to about 24 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and provides a mean release rate ofbuprenorphine of at least about 31 μg/hr, or of from about 36 to about45 μg/hr or from about 38 to about 42 μg/hr, and/or provides a nominalmean release rate of buprenorphine of about 40 μg/hr over about 168hours of administration.

According to one aspect, the invention relates to a method of treatingpain in a patient wherein a patient is treated with one appropriatelyselected TTS from a set of different transdermal therapeutic systems asdescribed in the previous paragraphs, wherein:

the first transdermal therapeutic system provides a mean AUCt of morethan 7,000 pg·hr/ml, preferably more than 8,000 pg·hr/ml, or of frommore than 7,000 pg·hr/ml to about 16,000 pg·hr/ml, or of from more than8,000 pg·hr/ml to about 16,000 pg·hr/ml over about 168 hours ofadministration after a single-dose administration to a subjectpopulation; andthe second transdermal therapeutic system provides a mean AUCt of morethan 14,000 pg·hr/ml, preferably of more than 16,000 pg·hr/ml, or offrom more than 14,000 pg·hr/ml to about 32,000 pg·hr/ml, or of from morethan 16,000 pg·hr/ml to about 32,000 pg·hr/ml over about 168 hours ofadministration after a single-dose administration to a subjectpopulation; andthe third transdermal therapeutic system provides a mean AUCt of morethan 28,000 pg·hr/ml, preferably of more than 32,000 pg·hr/ml, or offrom more than 28,000 pg·hr/ml to about 64,000 pg·hr/ml, or of from morethan 32,000 pg·hr/ml to about 64,000 pg·hr/ml over about 168 hours ofadministration after a single-dose administration to a subjectpopulation; andthe fourth transdermal therapeutic system provides a mean AUCt of morethan 42,000 pg·hr/ml, preferably of more than 48,000 pg·hr/ml, or offrom more than 42,000 pg·hr/ml to about 96,000 pg·hr/ml, or of from morethan 48,000 pg·hr/ml to about 96,000 pg·hr/ml over about 168 hours ofadministration after a single-dose administration to a subjectpopulation; andthe fifth transdermal therapeutic system provides a mean AUCt of morethan 62,000 pg·hr/ml, preferably of more than 64,000 pg·hr/ml, or offrom more than 62,000 pg·hr/ml to about 128,000 pg·hr/ml, or of frommore than 64,000 pg·hr/ml to about 128,000 pg·hr/ml over about 168 hoursof administration after a single-dose administration to a subjectpopulation.

According to one aspect, the invention relates to a method of treatmentdescribed in the previous paragraphs, wherein the transdermaltherapeutic system provides a mean AUCt per area of release of more than1,700 pg·hr/ml-cm², or of more than 1,900 pg·hr/ml-cm², or of more than2,300 pg·hr/ml-cm² over about 168 hours of administration after asingle-dose administration to a subject population or provides a meanAUCt per area of release of from more than 1,700 pg·hr/ml-cm² to about5,000 pg·hr/ml-cm², or of from more than 1,900 pg·hr/ml-cm² to about5,000 pg·hr/ml-cm², or of from more than 2,300 pg·hr/ml-cm² to about5,000 pg·hr/ml-cm² over about 168 hours of administration after asingle-dose administration to a subject population.

According to one aspect, the invention relates to a method of treatmentdescribed in the previous paragraphs, wherein the transdermaltherapeutic system provides an arithmetic mean tmax of from about 60 hrto about 120 hr, preferably from about 66 hr to less than 108 hr, orfrom about 72 hr to about 96 hr after a single-dose administration to asubject population.

Method of Manufacture

According to one further aspect, the invention relates to a method ofmanufacture of a transdermal therapeutic system for the transdermaladministration of buprenorphine, comprising the steps of

1. providing a buprenorphine-containing adhesive mixture or solutioncomprising

a) buprenorphine base or a pharmaceutically acceptable salt thereof

b) a carboxylic acid (e.g., levulinic acid),

c) a polymer-based pressure-sensitive adhesive, and

d) solvent (e.g., heptane and ethanol)

2. coating said buprenorphine-containing adhesive mixture or solution ona film (e.g., polyethylene terephthalate film) in an amount to providethe desired dry weight,3. drying said coated buprenorphine-containing adhesive mixture orsolution to provide a buprenorphine-containing adhesive layer with thedesired dry weight,4. laminating said buprenorphine-containing adhesive layer to a backinglayer (e.g., Scotchpak 1220 from 3M) to provide anbuprenorphine-containing self-adhesive layer structure,5. punching the individual systems from the buprenorphine-containingself-adhesive layer structure with the desired area of release, and6. optionally adhering to the individual systems an active-freeself-adhesive layer structure comprising also a backing layer and anactive agent-free pressure-sensitive adhesive layer and which is largerthan the individual systems of buprenorphine-containing self-adhesivelayer structure.

In step 1 of said method of manufacture preferably buprenorphine baseand levulinic acid are used and are suspended in ethanol andsubsequently combined with the polymer-based pressure-sensitive adhesivebased on polysiloxane in heptane to provide the buprenorphine-containingadhesive mixture or solution.

EXAMPLES

The present invention will now be more fully described with reference tothe accompanying examples. It should be understood, however, that thefollowing description is illustrative only and should not be taken inany way as a restriction of the invention.

Example 1

The composition of the buprenorphine base-containing adhesive solutionis summarized in Table 1 below.

TABLE 1 Amt/unit Ingredient (Trade Name) (kg) Buprenorphine base 3.65Levulinic acid 3.65 Ethanol 1.97 Polysiloxane adhesive in n-heptane 40.0Solids content of 73% by weight (BIO-PSA 7-4301 from Dow CorningHealthcare) n-heptane 2.87 Total 52.14

In a stainless steel vessel, 3.65 kg of buprenorphine were suspended in3.65 kg of levulinic acid and 1.97 kg of ethanol. With stirring, 40.0 kgof a polysiloxane adhesive in the form of a solution in n-heptane havinga solids content of 73% by weight and 2.87 kg of heptane were added. Themixture was stirred until the buprenorphine base was fully dissolved, togive 52.14 kg of a buprenorphine-containing adhesive solution with 7% ofbuprenorphine, with a solids content of 70% (buprenorphinebase-containing adhesive solution).

The buprenorphine base-containing adhesive solution was coated on anadhesive polyethylene terephthalate film (e.g., Scotchpak from 3M) usingan Erichsen coater and the solvent was removed by drying atapproximately 45° C. for 20 minutes. The coating thickness was chosensuch that removal of the solvents results in a coating weight of thematrix layer of 120 g/m². This results in the 10% by weight ofbuprenorphine base and 10% by weight of levulinic acid in this matrixlayer. The dried film was laminated with the backing layer (e.gScotchpak from 3M) to provide the buprenorphine-containing self-adhesivelayer structure.

The individual systems (TTS) were then punched from thebuprenorphine-containing self-adhesive layer structure. In specificembodiments a TTS as described above can be provided with a furtherself-adhesive layer of larger surface area, preferably with roundedcorners, comprising a pressure-sensitive adhesive matrix layer which isfree of active ingredient and has a preferably skin-colored backinglayer. This is of advantage when the TTS, on the basis of its physicalproperties alone, does not adhere sufficiently to the skin and/or whenthe buprenorphine-containing matrix layer, for the purpose of avoidingwaste, has pronounced corners (square or rectangular shapes).Theplasters are then punched out and sealed into pouches of the primarypackaging material.

Example 2

The composition of the buprenorphine base-containing adhesive solutionis summarized in Table 2 below.

TABLE 2 Amt/unit Ingredient (Trade Name) (kg) Buprenorphine base 3.65Levulinic acid 2.56 Ethanol 1.83 Polysiloxane adhesive in n-heptane41.49 Solids content of 73% by weight (BIO-PSA 7-4301 from Dow CorningHealthcare) n-heptane 2.61 Total 52.14

The process of manufacture was as described for Example 1. The coatingthickness was also chosen such that removal of the solvents results in acoating weight of the matrix layer of 120 g/m² and thus resulted in 10%by weight buprenorphine base and 7% by weight levulinic acid in thismatrix layer.

Example 3

The composition of the buprenorphine base-containing adhesive solutionis summarized in Table 3 below.

TABLE 3 Amt/unit Ingredient (Trade Name) (kg) Buprenorphine base 3.65Levulinic acid 3.65 Ethanol 1.97 Polysiloxane adhesive in n-heptane39.46 Solids content of 74% by weight (BIO-PSA 7-4201 from Dow CorningHealthcare) n-heptane 3.41 Total 52.14

The process of manufacture was as described for Example 1. The coatingthickness was also chosen such that removal of the solvents results in acoating weight of the matrix layer of 120 g/m² and thus resulted in 10%by weight buprenorphine base and 10% by weight levulinic acid in thismatrix layer.

Example 4

The composition of the buprenorphine base-containing adhesive solutionis summarized in Table 4 below.

TABLE 4 Amt/unit Ingredient (Trade Name) (kg) Buprenorphine base 3.65Levulinic acid 2.56 Ethanol 1.83 Polysiloxane adhesive in n-heptane40.93 Solids content of 74% by weight (BIO-PSA 7-4201 from Dow CorningHealthcare) n-heptane 3.17 Total 52.14

The process of manufacture was as described for Example 1. The coatingthickness was also chosen such that removal of the solvents results in acoating weight of the matrix layer of 120 g/m² and thus resulted in 10%by weight buprenorphine base and 7% by weight levulinic acid in thismatrix layer.

Comparative Example 5

In Comparative Example 5, a transdermal therapeutic system comprising anactive-agent-free skin contact layer on a buprenorphine-containingmatrix layer was prepared.

The composition of the buprenorphine base-containing adhesive solutionis summarized in Table 5a below and the composition of theactive-agent-free skin contact layer is summarized in Table 5b below.

TABLE 5a Amt/unit Ingredient (Trade Name) (kg) Buprenorphine base 0.42Levulinic acid 0.56 Ethanol 0.28 Polysiloxane adhesive in n-heptane 6.25Solids content of 74% by weight (BIO-PSA 7-4201 from Dow CorningHealthcare) n-heptane 0.49 Total 8.00

TABLE 5b Amt/unit Ingredient (Trade Name) (kg) Polyacrylate adhesiveprepared from 2- 3.69 ethylhexyl acrylate, vinyl acetate and 2-hydroxyethyl acrylate in Ethyl acetate Solids content 50.5% Ethylacetate 1.64 Total 5.33

In a stainless steel vessel, 0.42 kg of buprenorphine were suspended in0.56 kg of levulinic acid and 0.28 kg of ethanol. With stirring, 6.25 kgof a polysiloxane adhesive in the form of a solution in n-heptane havinga solids content of 74% by weight and 0.49 kg of heptane were added. Themixture was stirred until the buprenorphine base was fully dissolved, togive 8.00 kg of a buprenorphine-containing adhesive solution with 5.25%of buprenorphine, with a solids content of 70% (buprenorphinebase-containing adhesive solution).

For the skin contact layer, a polyacrylate adhesive prepared from2-ethylhexyl acrylate, vinyl acetate and 2-hydroxyethyl acrylate wereused. 3.69 kg of a solution of this adhesive, with a solids content of50.5% by weight, was admixed with 1.64 kg of ethyl acetate, followinghomogenization resulting in 5.33, kg of active-agent-free polyacrylatesolution with a solids content of 35% (buprenorphine base-free adhesivesolution)

The buprenorphine base-containing adhesive solution was coated on anadhesive polyethylene terephthalate film (e.g., Scotchpak from 3M) usingan Erichsen coater and the solvent was removed by drying atapproximately 50° C. for about 10 minutes to provide the buprenorphinebase-containing matrix layer. The coating thickness was chosen such thatremoval of the solvents results in a coating weight of the buprenorphinebase-containing matrix layer of 60 g/m². This results in the 7.5% byweight of buprenorphine base and 10% by weight of levulinic acid in thisbuprenorphine base-containing matrix layer. The dried film was laminatedwith the backing layer (e.g Scotchpak from 3M).

The active-agent-free polyacrylate adhesive solution was likewise coatedonto an adhesively treated film (the later protective film to be removedbefore the systems are used) and the organic solvents were removed toproduce the skin contact layer. The coating thickness of the resultingskin contact layer ought to amount, following removal of the solvents,to approximately 20 g/m². The adhesively treated film was then removedfrom the buprenorphine base-containing matrix layer produced first, andthe buprenorphine base-containing matrix layer was laminated onto theskin contact layer.

The individual systems (TTS) were then punched from thebuprenorphine-containing self-adhesive layer structure. In specificembodiments a TTS as described above can be provided with a furtherself-adhesive layer of larger surface area, preferably with roundedcorners, comprising a pressure-sensitive adhesive matrix layer which isfree of active ingredient and has a preferably skin-colored backinglayer. This is of advantage when the TTS, on the basis of its physicalproperties alone, does not adhere sufficiently to the skin and/or whenthe buprenorphine-containing matrix layer, for the purpose of avoidingwaste, has pronounced corners (square or rectangular shapes).Theplasters are then punched out and sealed into pouches of the primarypackaging material.

Example 6

In Example 6 the in-vitro releases and the corresponding skin permeationrates of Examples 1 to 4, Comparative Example 5 and Norspan® weredetermined by in vitro experiments in accordance with the OECD Guideline(adopted Apr. 13, 2004) carried out with a 9 ml Franz diffusion cell.Split thickness human skin from cosmetic surgeries (female breast, dateof birth 1989) was used. A dermatone was used to prepare skin to athickness of 800 μm, with an intact epidermis for all examples 1 to 4,Comparative Example 5 and the commercial product Norspan®. Diecuts withan area of 1.163 cm² were punched from examples 1 to 4 and ComparativeExample 5, and were each tested against diecuts of the commercialproduct Norspan®. The concentrations of buprenorphine in the receptormedium of the Franz cell (phosphate buffer solution pH 5.5 with 0.1%saline azide as antibacteriological agent) at a temperature of 32±1° C.were measured. The results are shown in Tables 6.1 to 6.8 and FIGS. 1 to4.

TABLE 6.1 Non-cumulative release [μg/cm²] n = 3 (SD) Elapsed time (hr)Example 1 Example 2 Example 3 Example 4 Norspan ® 0 0 0 0 0 0 8 4.063.53 2.35 3.33 3.19 (1.49) (0.70) (0.65) (1.89) (0.77) 24 44.60 33.6036.47 28.73 22.40 (16.99) (7.10) (10.19) (8.84) (3.76) 32 34.00 31.9336.47 22.10 13.83 (11.58) (13.14) (11.37) (5.54) (2.32) 48 73.77 58.1794.53 49.60 26.17 (20.38) (6.62) (20.48) (11.47) (2.46) 72 113.83 87.83131.67 74.10 32.43 (23.49) (8.76) (12.70) (14.25) (2.23) 144 272.00210.67 166.00 181.33 60.10 (22.52) (8.08) (28.62) (28.22) (2.02) 16878.30 65.60 26.73 60.97 17.17 (2.65) (6.25) (5.09) (9.69) (1.72)

TABLE 6.2 Non-cumulative release [μg/cm²] n = 3 (SD) Elapsed Comparativetime (hr) Example 5 Norspan ® 0 0 0 8 2.12 3.19 (1.44) (0.77) 24 28.6022.40 (10.19) (3.76) 32 26.37 13.83 (6.47) (2.32) 48 53.03 26.17 (5.80)(2.46) 72 58.47 32.43 (2.42) (2.23) 144 73.27 60.10 (4.63) (2.02) 16817.87 17.17 (1.35) (1.72)

TABLE 6.3 Mean non-cumulative skin permeation rate [μg/cm²-hr] n = 3(SD) Elapsed Sample time interval (hr) (hr) Example 1 Example 2 Example3 Example 4 Norspan ® 0 0 0 0 0 0 0 8 8 0.51 0.44 0.29 0.42 0.40 (0.19)(0.09) (0.08) (0.24) (0.10) 24 16 2.79 2.10 2.28 1.80 1.40 (1.06) (0.44)(0.64) (0.55) (0.24) 32 8 4.25 3.99 4.56 2.76 1.73 (1.45) (1.64) (1.42)(0.69) (0.29) 48 16 4.61 3.64 5.91 3.10 1.64 (1.27) (0.41) (1.28) (0.72)(0.15) 72 24 4.74 3.66 5.49 3.09 1.35 (0.98) (0.37) (0.53) (0.59) (0.09)144 72 3.78 2.93 2.31 2.52 0.83 (0.31) (0.11) (0.40) (0.39) (0.03) 16824 3.26 2.73 1.11 2.54 0.72 (0.11) (0.26) (0.21) (0.40) (0.07)

TABLE 6.4 Mean non-cumulative skin permeation rate [μg/cm²-hr] n = 3(SD) Sample Elapsed interval Comparative time (hr) (hr) Example 5Norspan ® 0 0 0 0 8 8 0.27 0.40 (0.18) (0.10) 24 16 1.79 1.40 (0.64)(0.24) 32 8 3.30 1.73 (0.81) (0.29) 48 16 3.31 1.64 (0.36) (0.15) 72 242.44 1.35 (0.10) (0.09) 144 72 1.02 0.83 (0.06) (0.03) 168 24 0.74 0.72(0.06) (0.07)

TABLE 6.5 Mean non-cumulative skin permeation rate [μg/cm²-hr] n = 3(SD) and per area of release [μg/hr] Norspan ® Elapsed Sample Area ofArea of time interval release release (hr) (hr) (cm²) Example 1 Example2 Example 3 Example 4 (25 cm²) 0 0 0 0 0 0 0 8 8 0.51 0.44 0.29 0.420.40 (0.19) (0.09) (0.08) (0.24) (0.10) 10 5.08 4.42 2.93 4.16 9.97 157.61 6.63 4.40 6.24 9.97 18.75 9.52 8.28 5.50 7.80 9.97 24 16 2.79 2.102.28 1.80 1.40 (1.06) (0.44) (0.64) (0.55) (0.24) 10 27.88 21.00 22.7917.96 35.00 15 41.81 31.50 34.19 26.94 35.00 18.75 52.27 39.38 42.7333.67 35.00 32 8 4.25 3.99 4.56 2.76 1.73 (1.45) (1.64) (1.42) (0.69)(0.29) 10 42.50 39.92 45.58 27.63 43.23 15 63.75 59.88 68.38 41.44 43.2318.75 79.69 74.84 85.47 51.80 43.23 48 16 4.61 3.64 5.91 3.10 1.64(1.27) (0.41) (1.28) (0.72) (0.15) 10 46.10 36.35 59.08 31.00 40.89 1569.16 54.53 88.63 46.50 40.89 18.75 86.45 68.16 110.78 58.13 40.89 72 244.74 3.66 5.49 3.09 1.35 (0.98) (0.37) (0.53) (0.59) (0.09) 10 47.4336.60 54.86 30.88 33.78 15 71.15 54.90 82.29 46.31 33.78 18.75 88.9368.62 102.86 57.89 33.78 144 72 3.78 2.93 2.31 2.52 0.83 (0.31) (0.11)(0.40) (0.39) (0.03) 10 37.78 29.26 23.06 25.19 20.87 15 56.67 43.8934.58 37.78 20.87 18.75 70.83 54.86 43.23 47.22 20.87 168 24 3.26 2.731.11 2.54 0.72 (0.11) (0.26) (0.21) (0.40) (0.07) 10 32.63 27.33 11.1425.40 17.88 15 48.94 41.00 16.71 38.10 17.88 18.75 61.17 51.25 20.8947.63 17.88

TABLE 6.6 Mean non-cumulative skin permeation rate [μg/cm²-hr] n = 3(SD) and per area of release [μg/hr] Norspan ® Elapsed Sample Area ofArea of time interval release Comp. release (hr) (hr) (cm²) Example 5(25 cm²) 0 0 0 0 8 8 0.27 0.40 (0.18) (0.10) 10 2.65 9.97 15 3.98 9.9718.75 4.98 9.97 24 16 1.79 1.40 (0.64) (0.24) 10 17.88 35.00 15 26.8135.00 18.75 33.52 35.00 32 8 3.30 1.73 (0.81) (0.29) 10 32.96 43.23 1549.44 43.23 18.75 61.80 43.23 48 16 3.31 1.64 (0.36) (0.15) 10 33.1540.89 15 49.72 40.89 18.75 62.15 40.89 72 24 2.44 1.35 (0.10) (0.09) 1024.36 33.78 15 36.54 33.78 18.75 45.68 33.78 144 72 1.02 0.83 (0.06)(0.03) 10 10.18 20.87 15 15.26 20.87 18.75 19.08 20.87 168 24 0.74 0.72(0.06) (0.07) 10 7.44 17.88 15 11.17 17.88 18.75 13.96 17.88

TABLE 6.7 Cumulative release after 168 hours of release [μg/cm²] n = 3Exam- Exam- Exam- Exam- Comparative ple 1 ple 2 ple 3 ple 4 Example 5Norspan ® 620.56 491.33 494.22 420.16 259.72 175.29

TABLE 6.8 Mean cumulative skin permeation rate over 168 hours[μg/cm²-hr] Exam- Exam- Exam- Exam- Comparative ple 1 ple 2 ple 3 ple 4Example 5 Norspan ® 3.69 2.92 2.94 2.50 1.55 1.04

Example 7

In Example 7, a pharmacokinetic study in healthy adult male and femalesubjects was conducted as part of a 2 stage, randomised, open-label,single-dose, 4-part crossover design pharmacokinetic study to assess thepharmacokinetics and potential of Example 1 TTS, Example 2 TTS andComparative Example 5 TTS formulations for equivalence to the existingcommercial product BuTrans®, also known as Norspant.

The study treatments were as follows:

Test Treatments:

-   -   Example 1 TTS—the amount of buprenorphine base being 12 mg; the        area of release being 10 cm²—applied for 7 consecutive days.    -   Example 2 TTS—the amount of buprenorphine base being 12 mg, the        area of release being 10 cm²—applied for 7 consecutive days.    -   Comparative Example 5 TTS—the amount of buprenorphine base being        6.75 mg; the area of release being 15 cm²—applied for 7        consecutive days.        Reference treatment: BuTrans® 20 μg/hr (the amount of        buprenorphine base being 20 mg; the area of release being 25        cm²)—applied for 7 consecutive days.

The treatments were each worn over a 7-day period. Each subject wasrandomised to both the order, and TTS site of the treatments to bedelivered over the study periods.

As this study was conducted in healthy human subjects, the opioidantagonist naltrexone was co-administered to reduce opioid-relatedadverse events. 50 mg naltrexone were administered with 100 ml of waterevery 12 hours beginning −13 hours prior to TTS application andcontinuing until 215 hours post-TTS application.

Subject Selection Number of Subjects

It was anticipated that approximately 32 subjects would be randomizedinto stage 1 of the study, with 26 subjects targeted to complete stage 1of the study. An adequate number of subjects were screened in thepre-treatment phase, i.e. within 21 days prior to the treatment phase toachieve this sample size.

Screening Procedure

Screening procedures were performed for all potential subjects at ascreening visit conducted within 21 days prior to the treatment phase,i.e. prior to Day −1 of study period 1. The following evaluations wereperformed after the subject has signed the study specific consent form:

-   -   Inclusion/Exclusion criteria    -   Demography (sex, date of birth, race) and body mass index (BMI)    -   Medical history (including confirmation of eligibility from the        subject's primary care physician)    -   Physical examination including height, weight, and body mass        index    -   Haematology (haemoglobin, red blood cell count, haematocrit,        platelets, white blood cell count and differential (neutrophils,        lymphocytes, monocytes, eosinophils and basophils))    -   Blood Chemistry (sodium, calcium, potassium, bicarbonate,        chloride, urea, creatinine, uric acid, albumin, total protein,        alkaline phosphatase, globulin, aspartate aminotransferase,        alanine aminotransferase, gamma glutamyl-transferase, total        bilirubin, direct bilirubin, glucose, inorganic phosphate,        lactate dehydrogenase, triglyceride and cholesterol)    -   Urinalysis (specific gravity, pH, protein, ketone, occult blood,        glucose; and additional microscopy analysis will be undertaken        if any abnormalities are detected to analyse for red blood        cells, white blood cells, epithelial cells, bacteria, casts, and        crystals)    -   Urine drugs of abuse (opiates, cocaine metabolites,        barbiturates, amphetamines, methadone, benzodiazepines,        phencyclidine, methamphetamine, tricyclic antidepressants and        cannabinoids) and alcohol test (urine or breath)    -   Serology testing (Human immunodeficiency virus (HIV), Hepatitis        B surface antigen (HBsAg), Hepatitis C antibody)    -   12-lead Electrocardiogram (ECG)    -   Serum pregnancy test for females of child-bearing potential    -   Serum FSH for post-menopausal females    -   Vital signs (Pulse oximetry/oxygen saturation (SpO₂), supine        respiration rate, supine blood pressure, supine pulse rate and        oral temperature)    -   Medication history and concomitant medications will also be        recorded.

Inclusion Criteria

Subjects who met the following criteria were included in the study.

-   -   1. Provide written informed consent.    -   2. Healthy male or female subjects aged 18 to 55 inclusive.    -   3. Female subjects who are sexually active or become sexually        active must be willing to use highly effective methods of        contraception throughout the study. A highly effective method of        birth control is defined as one which results in a low failure        rate (i.e. less than 1% per year) when used consistently and        correctly such as sterilisation, implants, injectables, combined        oral contraceptives, some IUDs (Intrauterine Device), or        vasectomised partner.    -   4. Female subjects including those up to 1 year post-menopausal        must have a negative serum pregnancy test.    -   5. Female subjects who have been post-menopausal for >1 year and        have elevated serum follicle-stimulating hormone (FSH) or are        treated with hormone replacement therapy (HRT).    -   6. Male subjects who are willing to use contraception with their        partners throughout the study and for 10 days after completion        of the study and agree to inform the Investigator if their        partner becomes pregnant during this time.    -   7. Body weight ranging from 55 to 100 kg and a BMI≧18 and ≦29.    -   8. Healthy and free of significant abnormal findings as        determined by medical history, physical examination, vital        signs, laboratory tests and ECG.    -   9. Willing to eat all the food supplied throughout the study.    -   10. The subject's primary care physician has confirmed within        the last 12 months that there is nothing in the subject's        medical history that would preclude their enrolment into a        clinical study.    -   11. Will refrain from strenuous exercise during the entire        study. They will not begin a new exercise program nor        participate in any unusually strenuous physical exertion.

Exclusion Criteria

The following criteria excluded potential subjects from the study.

-   -   1. Female subjects who are pregnant or lactating.    -   2. Any history of drug or alcohol abuse.    -   3. Any history of conditions that might interfere with drug        absorption, distribution, metabolism or excretion.    -   4. Use of opioid or opioid antagonist-containing medication in        the past 30 days.    -   5. Any history of frequent nausea or vomiting regardless of        aetiology.    -   6. Any history of seizures or symptomatic head trauma.    -   7. Participation in a clinical drug study during the 90 days        preceding the initial dose in this study or participation in any        other study during this study.    -   8. Any significant illness during the 4 weeks preceding entry        into this study.    -   9. A history of additional risk factors for Torsades de Pointes        (e.g. heart failure, hypokalemia, personal or family history of        long QT syndrome, syncope, or family history of sudden death).    -   10. Abnormal cardiac conditions including any of the following:        -   QTc interval greater than 450 msec at screening or at            check-in before first dosing.        -   Increase in QTc of more than 60 msec above pre-dose values            of each study period.    -   11. Use of medication within 5 times the half-life or minimum 14        days for prescription medication or 7 days for over-the-counter        preparations (including vitamins, herbal and/or mineral        supplements), whichever is longer, before the first dose of        study treatment and during the study (with the exception of the        continued use of HRT and contraceptives). Note: subjects taking        oral contraceptives containing CYP3A4 inhibitors such as        gestodene should be excluded as this may lead to elevated plasma        concentrations.    -   12. Refusal to abstain from caffeine or xanthine containing        beverages entirely until the last study PK sample has been        taken.    -   13. Weekly alcohol intake exceeding the equivalent of 14        units/week for females and 21 units/week for males.    -   14. Consumption of alcoholic beverages within 48 hours before        study drug administration, and refusal to abstain from alcohol        for the duration of the study confinement and for at least 72        hours after the last naltrexone dose.    -   15. History of smoking within 45 days of study drug        administration and refusal to abstain from smoking during the        study.    -   16. Blood or blood products donated within 90 days prior to        study drug administration or any time during the study, except        as required by this protocol.    -   17. Positive results of urine drug screen, alcohol test,        pregnancy test, HBsAg, Hepatitis C antibody, or HIV tests.    -   18. Known hypersensitivity or sensitivity to buprenorphine,        naltrexone or related compounds or any of the excipients or any        contraindications as detailed in the Summary of Product        Characteristics.    -   19. Clinically significant history of allergic reaction to wound        dressings or elastoplast.    -   20. Subjects with tattoos or any dermatological disorder at the        proposed sites of TTS application, or with a history of        eczema/cutaneous atrophy.    -   21. Subjects who will not allow hair to be removed at the        proposed TTS application sites which may prevent proper        placement of the TTS.    -   22. Refusal to allow their primary care physician to be        informed.

Subjects meeting all the inclusion criteria and none of the exclusioncriteria were randomized into the study.

Treatment Phase Procedures Randomisation

Randomisation was completed once all inclusion and exclusion criteriaare verified. Randomisation order was determined on a centralrandomisation list held at site (one list per site).

Subjects were randomised to the order of the treatments and the skin TTSapplication sites.

There are 4 possible TTS application sites:

-   -   Deltoid region of the non-dominant arm    -   Deltoid region of the dominant arm    -   Right upper back    -   Left upper back.

Check-in Procedures

On each day prior to treatment (e.g. Day −1 or Day 17), subjects werechecked in to the study unit. The following procedures were undertaken:

-   -   Review of consent and eligibility    -   Urine pregnancy test (Female subjects of child bearing potential        only)    -   Alcohol screen (by breath test) and    -   Urine drug screen as per screening visit    -   Naltrexone HCl dosing    -   Adverse events    -   Concomitant medications will be recorded.        Randomisation occurred once in the study on Day −1.

Study Procedures

The treatment phase included study periods with a single doseapplication. The following procedures were undertaken in each period:

-   -   Pre-dosing biochemistry (fasting) as per screening    -   TS application    -   Vital signs (supine respiration rate, supine blood pressure,        supine pulse rate)    -   SpO₂    -   Blood samples for drug concentration measurements obtained        pre-dose and at pre-specified times throughout the duration of        the study for each subject; TTS was removed at 168 hours after        TIS application; blood draw must be performed immediately prior        to TTS removal    -   12-lead ECG (taken before each TTS application, at 72, 120, and        168 hours after each TTS application in each study period and at        the Post-Study Medical)    -   Oral temperature was recorded at specified times throughout the        study    -   Adverse events; recorded throughout the study on an ongoing        basis whilst confined to the study unit and through open        questioning. Any recorded skin reactions will also be recorded        as adverse events.    -   Concomitant medications; recorded at Screening and throughout        the study    -   TTS site skin assessment and duration and observation        assessments; duration of TTS wear assessments were rated just        after application and then at the same time each day of TIS        wear. TTS observation assessments were performed just before TS        removal. Skin site reaction will be assessed 30 min after TTS        removal.

Where more than one procedure was scheduled at the same time-point, thefollowing order of procedures was ideally followed:

-   -   BTDS blood sample collection within ±5 minutes of scheduled        sampling time post dose. Pre-dose sample must be taken within        the hour before study drug dosing    -   Vital signs and ECG (within ±15 minutes of scheduled time)    -   Pulse oximetry (within ±15 minutes of scheduled time)    -   Skin reaction assessment at application site (within ±5 minutes        of scheduled time)    -   Duration of TTS wear observations (within ±30 minutes of        scheduled time)    -   Observation of TTS at removal (within −30 minutes of scheduled        time)    -   Food and fluids (start time within ±30 minutes of scheduled        time).

Throughout the Study Period when subjects had the TTS applied, they wereallowed to have a shower (not bath) but they had to refrain fromwashing, or rubbing the site of TTS application. The subjects shouldalso refrain from showering until the day after TTS application. The TTSwas removed on the eighth day of the Study Period following the blooddraw at 168 hours after TTS application.

Washout Period

There was a minimum 10 day washout period between removal of one TTS andapplication of another.

Confinement to the Study Unit

Subjects were confined to the study unit from Check-In on the day beforestudy drug administration until the time that the 192 hour post-TTSapplication procedures were completed. Subjects returned to the unit forthe 216, 240, 264 and 288 hours post-study procedures and the Post-StudyMedical. During confinement in the unit, subjects will receivestandardised meals.

Pharmacokinetic Measurements

Blood samples for pharmacokinetic assessments were obtained for eachsubject at predose and at 2, 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96,108, 120, 144, 168, 169, 172, 176, 180, 192, 216, 240, 264 and 288 hourspost-TTS application.

For each sample, 4 ml of blood were drawn into 4 ml tubes containingK₂EDTA solution, an anticoagulant. Samples were centrifuged within 30minutes of collection. Following centrifugation (1500 G, 4° C., 15minutes), the plasma was transferred, via pipette, into 2 labelled 3 mlpolypropylene tubes, and stored at −20° C. within 1 hour of collection.

Plasma concentrations of analytes were quantified by liquidchromatography—tandem mass spectrometric methodology (LC-MS/MS) using apreviously validated assay.

For each subject, the following pharmacokinetic parameters werecalculated based on the plasma concentrations of buprenorphine:

-   -   AUCt (pg·hr/ml)—the area under the plasma concentration-time        curve from hour 0 to the last measurable plasma concentration,        calculated by the linear trapezoidal method;    -   AUCINF (pg·hr/ml)—the area under the plasma concentration-time        curve extrapolated to infinity, calculated using the formula

${{AUCINF} = {{AUCt} + \frac{CLast}{LambdaZ}}},$

where CLast is the last measurable plasma concentration and LambdaZ isthe apparent terminal phase rate constant;

-   -   Cmax (pg/ml)—the maximum observed plasma concentration;    -   tmax (hr)—the time to maximum plasma concentration;    -   LambdaZ (l/hr)—the apparent terminal phase rate constant, where        LambdaZ is the magnitude of the slope of the linear regression        of the log concentration versus time profile during the terminal        phase;    -   t1/2Z (hr)—the apparent plasma terminal phase half-life        (whenever possible), where t1/2Z=(ln2)/LambdaZ.

Plasma concentration values below the level of quantitation were set toequal zero for the analysis.

AUC values were calculated using the linear trapezoidal method.

After removal of the BTDS, where possible, LambdaZ values were estimatedusing those points determined to be in the terminal log-linear phase.t1/2Z was determined from the ratio of ln 2 to LambdaZ.

Individual Subject Stopping Criteria

Subjects who met one or more of the following stopping criteria werediscontinued from the study:

-   -   Markedly Abnormal Liver Function Tests or Creatinine test    -   O₂ saturation 85% or less    -   Increase in QTc of more than 60 msec above pre-dose values of        each study period or QTc greater than 500 msec    -   Serious adverse drug reaction    -   Severe nausea and vomiting    -   Severe reaction at TTS site or a local reaction which        necessitates removal of the TTS or discontinuation of the        infusion    -   Systolic blood pressure (BP)≧180 mmHg    -   Heart rate (HR)≧140 bpm    -   Other BP and HR values and changes from baseline if associated        with cardiovascular compromise.

Study Restrictions

As per the inclusion/exclusion criteria, subjects had to be willing toeat all the food supplied throughout the study. Menus were standardisedwhile subjects are in the study unit. The menus were the same for eachstudy period. However, the menus for each day needed not be identical.Subjects had to consume only the food given to them while in the unit.Food and water will be restricted as follows:

-   -   Subjects were given an evening meal and snack following check-in        to the study unit on the day before dosing to be consumed >8        hours before dosing.    -   Subjects received a light breakfast 1 hour before commencement        of treatment.

There was free access to drinking water throughout the day, exceptwithin 30 minutes before vital sign measurements or commencement oftreatment. A low fat lunch (<30% fat), dinner, and an evening snack wereprovided at 4, 10, and 14 hours after TTS application. Drinks ofdecaffeinated tea or decaffeinated coffee were supplied with meals.

-   -   Meals were provided at the same time each day (as on Day 1).        There was free access to drinking water and de-caffeinated        drinks throughout the day, except within 30 minutes before vital        sign measurements.    -   Breakfast will be optional after all study procedures have been        completed.

Subjects had to abstain from smoking within 45 days of study drugadministration and during the entire study. Subjects had to abstain fromalcohol from 48 hours before the first study drug administration until72 hours after the last naltrexone dose of the last study period.Caffeine or xanthine containing food or beverages were not permittedduring the study from check-in before treatment, until after the laststudy pharmacokinetic sample has been taken.

Follow-Up Period

Subjects that completed the treatment phase or who discontinuedtreatment early were followed up within 7 to 10 days after the Subject'slast visit/dose of study medication.

Study Completion Procedures

Subjects that completed the Treatment Phase carried out the followingCompletion/Discontinuation Visit procedures:

-   -   Subjects attended a Post-Study Medical Visit 7 to 10 days after        removal of their last TTS if this was the last treatment        received in the case of completion/discontinuation from the        study.    -   Safety was monitored and Post-Study Medical procedures were        carried out including the following:        -   Physical examination including weight measurement        -   Haematology (as for screening visit)        -   Blood chemistry (as for screening visit)        -   Urinalysis (as for screening visit)        -   Serum pregnancy test for females of child bearing potential        -   12-lead ECG        -   Vital signs (supine respiration rate, supine blood pressure,            supine pulse rate)        -   Pulse oximetry        -   Oral temperature        -   Review of adverse events        -   Review of concomitant therapy.

The results of this study are shown in in FIG. 5 and Tables 7.1 to 7.11below:

TABLE 7.1 Statistical results for pharmacokinetic parameters (fullanalysis population): Example 1 TTS (12 mg/10 cm²) and Example 2 TTS (12mg/10 cm²) relative to BuTrans ® (20 mg/25 cm²) Example 1 TTS Example 2TTS BuTrans ® Cmax (pg/ml) n^(a) 26 28 28 Mean^(b) 312.20 301.28 383.63SD^(c) 169.48 163.41 176.63 SE^(d) 33.24 30.88 33.38 GeoMean^(e) 270.93261.30 346.47 log SD^(f) 0.552 0.560 0.467 log SE^(g) 0.108 0.106 0.088Min^(h) 92.80 80.80 120.03 Median^(i) 260.87 283.00 376.74 Max^(k)708.13 829.94 872.38 AUCt (pg · hr/ml) n^(a) 26 28 28 Mean^(b) 29682.1131223.49 44323.44 SD^(c) 13814.72 15305.33 19273.58 SE^(d) 2709.292892.44 3642.36 GeoMean^(e) 26904.86 27468.57 40613.23 log SD^(f) 0.4520.534 0.428 log SE^(g) 0.089 0.101 0.081 Min^(h) 12074.7 9263.5 14312.1Median^(i) 25820.52 26981.95 40866.71 Max^(k) 64020.0 63874.7 100315.6AUCINF (pg · hr/ml) n^(a) 24 23 25 Mean^(b) 30689.03 33483.34 45108.89SD^(c) 14387.48 15193.45 19782.01 SE^(d) 2936.83 3168.05 3956.40GeoMean^(e) 27724.63 30024.46 41273.54 log SD^(f) 0.462 0.495 0.434 logSE^(g) 0.094 0.103 0.087 Min^(h) 12498.8 10821.7 14619.5 Median^(i)26437.33 32248.48 43282.61 Max^(k) 64907.6 64670.1 101394.2 tmax (hr)n^(a) 26 28 28 Mean^(b) 79.12 72.00 81.93 SD^(c) 34.50 31.33 37.56SE^(d) 6.77 5.92 7.10 Min^(h) 36.00 24.00 24.00 Median^(i) 78.00 66.0072.00 Max^(k) 172.00 144.00 169.00 LambdaZ (1/hr) n^(a) 24 23 25Mean^(b) 0.0179 0.0192 0.0175 SD^(c) 0.0079 0.0087 0.0068 SE^(d) 0.00160.0018 0.0014 Min^(h) 0.007 0.008 0.007 Median^(i) 0.0165 0.0165 0.0164Max^(k) 0.043 0.044 0.041 t½Z (hr) n^(a) 24 23 25 Mean^(b) 44.77 42.7544.73 SD^(c) 16.96 17.66 16.82 SE^(d) 3.46 3.68 3.36 Min^(h) 15.94 15.9216.75 Median^(i) 41.96 41.92 42.22 Max^(k) 93.79 83.91 98.27 ^(a)n =number of subjects with data available (non-zero values). ^(b)Mean =arithmetic mean; the sum of all the values of observations divided bythe total number of observations. ^(c)SD = standard deviation. ^(d)SE =standard error. ^(e)GeoMean = geometric mean; the mean of the logtransformed data backtransformed to the original scale. ^(f)log SD =standard deviation of the log transformed data. ^(g)log SE = standarderror of the log transformed data. ^(h)Min = minimum value. ^(i)Median =middle value when the list of values is ranked. ^(k)Max = maximum value.

TABLE 7.2 Statistical results for pharmacokinetic parameters (fullanalysis population): Comparative Example 5 TTS (6.75 mg/15 cm²)relative to BuTrans ® (20 mg/25 cm²) Cmax (pg/ml) AUCt (pg · hr/ml)Comp. Comp. Example 5 Example 5 TTS BuTrans ® TTS BuTrans ® n^(a) 28 2828 28 Mean^(b) 288.29 383.63 27709.30 44323.44 SD^(c) 137.67 176.6313213.42 19273.58 SE^(d) 26.02 33.38 2497.10 3642.36 GeoMean^(e) 258.05346.47 25025.91 46613.23 log SD^(f) 0.484 0.467 0.456 0.428 log SE^(g)0.091 0.088 0.086 0.081 Min^(h) 111.98 120.03 11539.6 14312.1 Median^(i)254.25 376.74 24401.87 40866.71 Max^(k) 595.80 872.38 57931.7 100315.6AUCINF (pg · hr/ml) tmax (hr) Comp. Comp. Example 5 Example 5 TTSBuTrans ® TTS BuTrans ® n^(a) 26 25 28 28 Mean^(b) 28850.38 45108.89108.21 81.93 SD^(c) 13805.37 19782.01 38.02 37.56 SE^(d) 2707.46 3956.407.19 7.10 GeoMean^(e) 26019.04 41273.54 NA^(l) NA^(l) log SD^(f) 0.4610.434 NA^(l) NA^(l) log SE^(g) 0.090 0.087 NA^(l) NA^(l) Min^(h)11702.00 14619.5 48.00 24.00 Median^(i) 25186.06 43282.61 96.00 72.00Max^(k) 60731.70 101394.2 169.00 169.00 LambdaZ (1/hr) t½Z (hr) Comp.Comp. Example 5 Example 5 TTS BuTrans ® TTS BuTrans ® n^(a) 26 25 26 25Mean^(b) 0.0172 0.0175 50.38 44.73 SD^(c) 0.0090 0.0068 27.38 16.82SE^(d) 0.0018 0.0014 5.37 3.36 Min^(h) 0.004 0.0070 13.80 16.75Median^(i) 0.0157 0.0164 44.14 42.22 Max^(k) 0.050 0.041 154.54 98.27^(a)n = number of subjects with data available (non-zero values).^(b)Mean = arithmetic mean; the sum of all the values of observationsdivided by the total number of observations. ^(c)SD = standarddeviation. ^(d)SE = standard error. ^(e)GeoMean = geometric mean; themean of the log transformed data backtransformed to the original scale.^(f)log SD = standard deviation of the log transformed data. ^(g)log SE= standard error of the log transformed data. ^(h)Min = minimum value.^(i)Median = middle value when the list of values is ranked. ^(k)Max =maximum value. ^(l)NA = not applicable.

TABLE 7.3 Mean AUCt per area of release (pg · hr/ml-cm²) Exam- Exam-Comparative ple 1 ple 2 Example 5 TTS TTS TTS BuTrans ® 2690.49 2746.861668.39 1624.53

TABLE 7.4 Summary of mixed model^(a) for pharmacokinetic parametersCmax, AUCt, and AUCINF (full analysis population): Example 1 TTS (12 mg)relative to BuTrans ® (20 mg) LS Mean^(c) LS Mean^(b) Ratio Exam-Exampel 1 90% ple 1 TTS/ Confidence n^(d) TTS BuTrans ® BuTrans ® (%)Interval (%) Cmax 25 278.48 352.93 78.90^(e) [66.65, 93.41] AUCt 2527289.42 42335.49 64.46^(f) [55.05, 75.48] AUCINF 20 26968.66 40541.3866.52^(f) [58.09, 76.18] ^(a)Data analysed using a mixed effects linearmodel with treatment, actual sequence and period as fixed effects andsubject within sequence as random effect. The analyses only considersubjects who completed both periods of the respective treatmentcomparison. ^(b)Least square mean; back-transformed from log scale tolinear scale. ^(c)Least square mean; back-transformed from difference onlog scale to ratio on linear scale. ^(d)Number of subjects with data forboth Example 1 and BuTrans ® available. ^(e)equivalent to relative Cmaxratio. ^(f)equivalent to relative bioavailability.

TABLE 7.5 Summary of mixed model^(a) for pharmacokinetic parametersCmax, AUCt, and AUCINF (full analysis population): Example 2 TTS (12 mg)relative to BuTrans ® (20 mg) LS Mean^(c) LS Mean^(b) Ratio Exam-Exampel 2 90% ple 2 TTS/ Confidence n^(d) TTS BuTrans ® BuTrans ® (%)Interval (%) Cmax 24 267.94 338.34 79.19^(e) [69.03, 90.86] AUCt 2428021.68 39507.72 70.93^(f) [61.99, 81.15] AUCINF 16 31910.44 42095.1175.81 [62.53, 91.90] ^(a)Data analysed using a mixed effects linearmodel with treatment, actual sequence and period as fixed effects andsubject within sequence as random effect. The analyses only considersubjects who completed both periods of the respective treatmentcomparison. ^(b)Least square mean; back-transformed from log scale tolinear scale. ^(c)Least square mean; back-transformed from difference onlog scale to ratio on linear scale. ^(d)Number of subjects with data forboth Example 2 and BuTrans ® available. ^(e)equivalent to relative Cmaxratio. ^(f)equivalent to relative bioavailability.

TABLE 7.6 Summary of mixed model^(a) for pharmacokinetic parametersCmax, AUCt, and AUCINF (full analysis population): Comparative Example 5TTS (6.75 mg) relative to BuTrans ® (20 mg) LS Mean^(b) LS Mean^(c)Comp. Ratio Comp. Exam- Exampel 5 90% ple 5 TTS/ Confidence n^(d) TTSBuTrans ® BuTrans ® (%) Interval (%) Cmax 26 274.03 348.94 78.53^(e)[65.43, 94.26] AUCt 26 26037.56 41121.81 63.32^(f) [52.64, 76.16] AUCINF21 26782.27 41460.21 64.60^(f) [51.62, 80.84] ^(a)Data analysed using amixed effects linear model with treatment, actual sequence and period asfixed effects and subject within sequence as random effect. The analysesonly consider subjects who completed both periods of the respectivetreatment comparison. ^(b)Least square mean; back-transformed from logscale to linear scale. ^(c)Least square mean; back-transformed fromdifference on log scale to ratio on linear scale. ^(d)Number of subjectswith data for both Comparative Example 5 TTS and BuTrans ® available.^(e)equivalent to relative Cmax ratio. ^(f)equivalent to relativebioavailability.

TABLE 7.7 Summary of mixed model^(a) for pharmacokinetic parameter t½Z(full analysis population): Example 1 TTS (12 mg) relative to BuTrans ®(20 mg) LS Mean^(b) 90% Exampel 1 - Confidence n^(c) Example 1 BuTrans ®BuTrans ® Interval t½Z 20 42.69 42.62 0.07 [−4.38, 4.53] ^(a)Dataanalysed using a mixed effects linear model with treatment, actualsequence and period as fixed effects and subject within sequence asrandom effect. The analyses only consider subjects who completed bothperiods of the respective treatment comparison. ^(b)Least square mean.^(c)Number of subjects with data for both Example 1 and BuTrans ®available.

TABLE 7.8 Summary of mixed model^(a) for pharmacokinetic parameter t½Z(full analysis population): Example 2 TTS (12 mg) relative to BuTrans ®(20 mg) LS Mean^(b) 90% Exampel 2 - Confidence n^(c) Example 2 BuTrans ®BuTrans ® Interval t½Z 16 43.16 44.63 −1.47 [−10.63, 7.70] ^(a)Dataanalysed using a mixed effects linear model with treatment, actualsequence and period as fixed effects and subject within sequence asrandom effect. The analyses only consider subjects who completed bothperiods of the respective treatment comparison. ^(b)Least square mean.^(c)Number of subjects with data for both Example 2 and BuTrans ®available.

TABLE 7.9 Summary of mixed model^(a) for pharmacokinetic parametert½Z(full analysis population): Comparative Example 5 TTS (6.75 mg)relative to BuTrans ® (20 mg) LS Mean^(b) Comp. Comp. Example 5 90%Example 5 TTS- Confidence n^(c) TTS BuTrans ® BuTrans ® Interval t½Z 2152.64 42.59 10.05 [0.32, 19.78] ^(a)Data analysed using a mixed effectslinear model with treatment, actual sequence and period as fixed effectsand subject within sequence as random effect. The analyses only considersubjects who completed both periods of the respective treatmentcomparison. ^(b)Least square mean. ^(c)Number of subjects with data forboth Comparative Example 5 TTS and BuTrans ® available.

TABLE 7.10 Bioequivalence assessment relative to BuTrans ® for a 36%increase^(a) in plasma concentrations for Example 2 TTS Ratio Exampel 290% Confidence TTS/BuTrans ® (%) Interval (%) ln(Cmax) 106.93 [91.92;124.41] ln(AUCt) 95.37 [82.07; 110.82] ln(AUCINF) 100.56 [85.63; 118.10]^(a)Calculated based on the individual subject data of Example 2 TTS (12mg).

An increase of about 36% in plasma concentrations for Example 2 TISwould be expected to render the TTS bioequivalent to BuTrans® (20 mg/25cm²) also known as Norspan®, in a single dose study.

TABLE 7.11 Bioequivalence assessment relative to BuTrans ® for a 50%increase^(a) in plasma concentrations for Comparative Example 5 TTSRatio Comp. Exampel 5 90% Confidence TTS/BuTrans ® (%) Interval (%)ln(Cmax) 119.77 [102.53; 139.91]  ln(AUCt) 97.43 [83.70; 113.41]ln(AUCINF) 101.14 [85.04; 120.29] ^(a)Calculated based on the individualsubject data of Comparative Example 5 TTS (6.75 mg).

Even an increase of about 50% in plasma concentrations for ComparativeExample 5 TTS would not be expected to render the TITS bioequivalent toBuTrans® (20 mg/25 cm²), also known as Norspan®, in a single dose study.

The Invention relates in particular to the following further items:

1. Transdermal therapeutic system for the transdermal administration ofbuprenorphine, comprising a buprenorphine-containing self-adhesive layerstructure comprising

-   -   A) a buprenorphine-impermeable backing layer, and    -   B) a buprenorphine-containing pressure-sensitive adhesive layer        on said buprenorphine-impermeable backing layer, the adhesive        layer comprising        -   a) at least one polymer-based pressure-sensitive adhesive,        -   b) an analgesically effective amount of buprenorphine base            or a pharmaceutically acceptable salt thereof, and        -   c) a carboxylic acid selected from the group consisting of            oleic acid, linoleic acid, linolenic acid, levulinic acid            and mixtures thereof, in an amount sufficient so that said            analgesically effective amount of buprenorphine is            solubilized therein to form a mixture, and the carboxylic            acid buprenorphine mixture forms dispersed deposits in the            said pressure-sensitive adhesive,            wherein said buprenorphine-containing pressure-sensitive            adhesive layer is the skin contact layer.            2. Transdermal therapeutic system in accordance with item 1,            wherein said buprenorphine is present in the form of            buprenorphine base.            3. Transdermal therapeutic system in accordance with item 1,            wherein said carboxylic acid is levulinic acid.            4. Transdermal therapeutic system in accordance with item 1,            wherein said buprenorphine is present in the form of            buprenorphine base and said carboxylic acid is levulinic            acid.            5. Transdermal therapeutic system in accordance with item 1,            wherein said polymer-based pressure-sensitive adhesive is            based on polysiloxanes or polyisobutylenes.            6. Transdermal therapeutic system in accordance with item 1,            wherein said polymer-based pressure-sensitive adhesive is            based on polysiloxanes.            7. Transdermal therapeutic system in accordance with item 1,            wherein said buprenorphine is present in the form of            buprenorphine base, said carboxylic acid is levulinic acid            and the polymer-based pressure-sensitive adhesive is based            on polysiloxanes.            8. Transdermal therapeutic system in accordance with any one            of items 1 to 7, the amount of said buprenorphine contained            in the transdermal therapeutic system ranging from about 1            mg to about 4 mg buprenorphine base or an equimolar amount            of a pharmaceutically acceptable salt thereof, or            about 3.5 mg to about 8 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof, or            about 6.5 mg to about 16 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof, or            about 11.5 mg to about 24 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof, or            about 15 mg to about 32 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof.            9. Transdermal therapeutic system in accordance with item 8,            the amount of said buprenorphine contained in the            transdermal therapeutic system ranging from about 1 mg to            about 3.5 mg buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof, or            about 3.5 mg to about 7 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof, or            about 6.5 mg to about 14 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof, or            about 11.5 mg to about 21 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof, or            about 15 mg to about 28 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof.            10. Transdermal therapeutic system in accordance with item            8, the amount of said buprenorphine contained in the            transdermal therapeutic system ranging from about 1 mg to            about 3 mg buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof, or            about 3.5 mg to about 6 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof, or            about 6.5 mg to about 11 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof, or            about 11.5 mg to about 14 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof, or            about 15 mg to about 24 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof.            11. Transdermal therapeutic system in accordance with any            one of items 1 to 10, the size of said            buprenorphine-containing pressure-sensitive adhesive layer            providing the area of release ranging from about 1 cm² to            about 4.8 cm², or            about 3 cm² to about 9.5 cm².            about 6 cm² to about 19 cm²,            about 12 cm² to about 28.5 cm², or            about 16 cm² to about 38 cm².            12. Transdermal therapeutic system in accordance with item            11, the size of said buprenorphine-containing            pressure-sensitive adhesive layer providing the area of            release ranging from about 1 cm² to about 4.5 cm², or            about 3 cm² to about 9 cm²,            about 6 cm² to about 18 cm²,            about 12 cm² to about 27 cm², or            about 16 cm² to about 35 cm².            13. Transdermal therapeutic system in accordance with item            11, the size of said buprenorphine-containing            pressure-sensitive adhesive layer providing the area of            release ranging from about 2.5 cm² to about 4 cm²,            about 5 cm² to about 8 cm²,            about 10 cm² to about 16 cm²,            about 17 cm² to about 23 cm², or            about 23.5 cm² to about 32 cm².            14. Transdermal therapeutic system in accordance with any            one of items 1 to 7, the size of said            buprenorphine-containing pressure-sensitive adhesive layer            providing the area of release ranging from about 1 cm² to            about 4.8 cm² and the amount of said buprenorphine contained            in the transdermal therapeutic system ranging from about 1            mg to about 4 mg buprenorphine base or an equimolar amount            of a pharmaceutically acceptable salt thereof.            15. Transdermal therapeutic system in accordance with any            one of items 1 to 7, the size of said            buprenorphine-containing pressure-sensitive adhesive layer            providing the area of release ranging from about 3 cm² to            about 9.5 cm², and the amount of said buprenorphine            contained in the transdermal therapeutic system ranging from            about 3.5 mg to about 8 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof.            16. Transdermal therapeutic system in accordance with any            one of items 1 to 7, the size of said            buprenorphine-containing pressure-sensitive adhesive layer            providing the area of release ranging from about 6 cm² to            about 19 cm² and the amount of said buprenorphine contained            in the transdermal therapeutic system ranging from about 6.5            mg to about 16 mg buprenorphine base or an equimolar amount            of a pharmaceutically acceptable salt thereof.            17. Transdermal therapeutic system in accordance with any            one of items 1 to 7, the size of said            buprenorphine-containing pressure-sensitive adhesive layer            providing the area of release ranging from about 12 cm² to            about 28.5 cm², and the amount of said buprenorphine            contained in the transdermal therapeutic system ranging from            about 11.5 mg to about 24 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof.            18. Transdermal therapeutic system in accordance with any            one of items 1 to 7, the size of said            buprenorphine-containing pressure-sensitive adhesive layer            providing the area of release ranging from about 16 cm² to            about 38 cm², and the amount of said buprenorphine contained            in the transdermal therapeutic system ranging from            about 15 mg to about 32 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof.            19. Transdermal therapeutic system in accordance with any            one of items 1 to 7, the size of said            buprenorphine-containing pressure-sensitive adhesive layer            providing the area of release ranging from about 1 cm² to            about 4.5 cm² and the amount of said buprenorphine contained            in the transdermal therapeutic system ranging from about 1            mg to about 3.5 mg buprenorphine base or an equimolar amount            of a pharmaceutically acceptable salt thereof            20. Transdermal therapeutic system in accordance with any            one of items 1 to 7, the size of said            buprenorphine-containing pressure-sensitive adhesive layer            providing the area of release ranging from about 3 cm² to            about 9 cm², and the amount of said buprenorphine contained            in the transdermal therapeutic system ranging from about 3.5            mg to about 7 mg buprenorphine base or an equimolar amount            of a pharmaceutically acceptable salt thereof.            21. Transdermal therapeutic system in accordance with any            one of items 1 to 7, the size of said            buprenorphine-containing pressure-sensitive adhesive layer            providing the area of release ranging from about 6 cm² to            about 18 cm² and the amount of said buprenorphine contained            in the transdermal therapeutic system ranging from about 6.5            mg to about 14 mg buprenorphine base or an equimolar amount            of a pharmaceutically acceptable salt thereof.            22. Transdermal therapeutic system in accordance with any            one of items 1 to 7, the size of said            buprenorphine-containing pressure-sensitive adhesive layer            providing the area of release ranging from about 12 cm² to            about 27 cm², and the amount of said buprenorphine contained            in the transdermal therapeutic system ranging from about            11.5 mg to about 21 mg buprenorphine base or an equimolar            amount of a pharmaceutically acceptable salt thereof.            23. Transdermal therapeutic system in accordance with any            one of items 1 to 7, the size of said            buprenorphine-containing pressure-sensitive adhesive layer            providing the area of release ranging from about 16 cm² to            about 35 cm², and the amount of said buprenorphine contained            in the transdermal therapeutic system ranging from about 15            mg to about 28 mg buprenorphine base or an equimolar amount            of a pharmaceutically acceptable salt thereof.            24. Transdermal therapeutic system in accordance with any            one of items 1 to 7, the size of said            buprenorphine-containing pressure-sensitive adhesive layer            providing the area of release ranging from about 2.5 cm² to            about 4 cm² and the amount of said buprenorphine contained            in the transdermal therapeutic system ranging from about 1            mg to about 3 mg buprenorphine base or an equimolar amount            of a pharmaceutically acceptable salt thereof.            25. Transdermal therapeutic system in accordance with any            one of items 1 to 7, the size of said            buprenorphine-containing pressure-sensitive adhesive layer            providing the area of release ranging from about 5 cm² to            about 8 cm², and the amount of said buprenorphine contained            in the transdermal therapeutic system ranging from about 3.5            mg to about 6 mg buprenorphine base or an equimolar amount            of a pharmaceutically acceptable salt thereof.            26. Transdermal therapeutic system in accordance with any            one of items 1 to 7, the size of said            buprenorphine-containing pressure-sensitive adhesive layer            providing the area of release ranging from about 10 cm² to            about 16 cm² and the amount of said buprenorphine contained            in the transdermal therapeutic system ranging from about 6.5            mg to about 11 mg buprenorphine base or an equimolar amount            of a pharmaceutically acceptable salt thereof.            27. Transdermal therapeutic system in accordance with any            one of items 1 to 7, the size of said            buprenorphine-containing pressure-sensitive adhesive layer            providing the area of release ranging from about 17 cm² to            about 23 cm², and the amount of said buprenorphine contained            in the transdermal therapeutic system ranging from about            11.5 mg to about 14 mg buprenorphine base or an equimolar            amount of a pharmaceutically acceptable salt thereof.            28. Transdermal therapeutic system in accordance with any            one of items 1 to 7, the size of said            buprenorphine-containing pressure-sensitive adhesive layer            providing the area of release ranging from about 23.5 cm² to            about 32 cm², and the amount of said buprenorphine contained            in the transdermal therapeutic system ranging from about 15            mg to about 24 mg buprenorphine base or an equimolar amount            of a pharmaceutically acceptable salt thereof.            29. Transdermal therapeutic system in accordance with any            one of items 1 to 7, the amount of said buprenorphine            contained in the transdermal therapeutic system ranging from            about about 1 mg to about 4 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof.            30. Transdermal therapeutic system in accordance with item            29, the amount of said buprenorphine contained in the            transdermal therapeutic system ranging from about 1 mg to            about 3.5 mg buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            31. Transdermal therapeutic system in accordance with item            29, the amount of said buprenorphine contained in the            transdermal therapeutic system ranging from about 1 mg to            about 3 mg buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            32. Transdermal therapeutic system in accordance with any            one of items 29 to 31, the size of said            buprenorphine-containing pressure-sensitive adhesive layer            providing the area of release ranging from about 1 cm² to            about 4.8 cm².            33. Transdermal therapeutic system in accordance with item            32, the size of said buprenorphine-containing            pressure-sensitive adhesive layer providing the area of            release ranging from about 1 cm² to about 4.5 cm².            34. Transdermal therapeutic system in accordance with item            32, the size of said buprenorphine-containing            pressure-sensitive adhesive layer providing the area of            release ranging from about 2.5 cm² to about 4 cm².            35. Transdermal therapeutic system in accordance with any            one of items 14, 19, 24, or 29 to 34, said transdermal            therapeutic system providing a mean AUCt of more than 7,000            pg·hr/ml over about 168 hours of administration after a            single-dose administration to a subject population.            36. Transdermal therapeutic system in accordance with item            35, said transdermal therapeutic system providing a mean            AUCt of more than 8,000 pg·hr/ml over about 168 hours of            administration after a single-dose administration to a            subject population.            37. Transdermal therapeutic system in accordance with item            35, said transdermal therapeutic system providing a mean            AUCt of from more than 8,000 pg·hr/ml to about 16,000            pg·hr/ml over about 168 hours of administration after a            single-dose administration to a subject population.            38. Transdermal therapeutic system in accordance with any            one of items 14, 19, 24, or 29 to 37, wherein the            transdermal therapeutic system provides a nominal mean            release rate of about 5 μg/hr over about 168 hours of            administration.            39. Transdermal therapeutic system in accordance with any            one of items 14, 19, 24, or 29 to 37, wherein the            transdermal therapeutic system provides a mean release rate            ranging from about 2.5 to about 7.5 μg/hr over about 168            hours of administration.            40. Transdermal therapeutic system in accordance with any            one of items 14, 19, 24, or 29 to 39, wherein buprenorphine            is present in the form of buprenorphine base and wherein the            transdermal therapeutic system when tested in a comparative            clinical study is bioequivalent to the commercial product            BuTrans@ having an area of release of 6.25 cm².            41. Transdermal therapeutic system in accordance with any            one of items 1 to 7, the amount of said buprenorphine            contained in the transdermal therapeutic system ranging from            about 3.5 mg to about 8 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof.            42. Transdermal therapeutic system in accordance with item            41, the amount of said buprenorphine contained in the            transdermal therapeutic system ranging from about 3.5 mg to            about 7 mg buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            43. Transdermal therapeutic system in accordance with item            41, the amount of said buprenorphine contained in the            transdermal therapeutic system ranging from about 3.5 mg to            about 6 mg buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            44. Transdermal therapeutic system in accordance with any            one of items 41 to 43, the size of said            buprenorphine-containing pressure-sensitive adhesive layer            providing the area of release ranging from about 3 cm² to            about 9.5 cm².            45. Transdermal therapeutic system in accordance with item            44, the size of said buprenorphine-containing            pressure-sensitive adhesive layer providing the area of            release ranging from about 3 cm² to about 9 cm².            46. Transdermal therapeutic system in accordance with item            44, the size of said buprenorphine-containing            pressure-sensitive adhesive layer providing the area of            release ranging from about 5 cm² to about 8 cm².            47. Transdermal therapeutic system in accordance with any            one of items 15, 20, 25, or 41 to 46, said transdermal            therapeutic system providing a mean AUCt of more than 14,000            pg·hr/ml over about 168 hours of administration after a            single-dose administration to a subject population.            48. Transdermal therapeutic system in accordance with item            47, said transdermal therapeutic system providing a mean            AUCt of more than 16,000 pg·hr/ml over about 168 hours of            administration after a single-dose administration to a            subject population.            49. Transdermal therapeutic system in accordance with item            47, said transdermal therapeutic system providing a mean            AUCt of from more than 16,000 pg·hr/ml to about 32,000            pg·hr/ml over about 168 hours of administration after a            single-dose administration to a subject population.            50. Transdermal therapeutic system in accordance with any            one of items 15, 20, 25, or 41 to 49, wherein the            transdermal therapeutic system provides a nominal mean            release rate of about 10 μg/hr over about 168 hours of            administration.            51. Transdermal therapeutic system in accordance with any            one of items 15, 20, 25, or 41 to 49, wherein the            transdermal therapeutic system provides a mean release rate            ranging from about 8 to about 12 μg/hr over about 168 hours            of administration.            52. Transdermal therapeutic system in accordance with any            one of items 15, 20, 25, or 41 to 51, wherein buprenorphine            is present in the form of buprenorphine base and wherein the            transdermal therapeutic system when tested in a comparative            clinical study is bioequivalent to the commercial product            BuTrans® having an area of release of 12.5 cm².            53. Transdermal therapeutic system in accordance with any            one of items 1 to 7, the amount of said buprenorphine            contained in the transdermal therapeutic system ranging from            about 6.5 mg to about 16 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof.            54. Transdermal therapeutic system in accordance with item            53, the amount of said buprenorphine contained in the            transdermal therapeutic system ranging from about 6.5 mg to            about 14 mg buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            55. Transdermal therapeutic system in accordance with item            53, the amount of said buprenorphine contained in the            transdermal therapeutic system ranging from about 6.5 mg to            about 11 mg buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            56. Transdermal therapeutic system in accordance with any            one of items 53 to 55, the size of said            buprenorphine-containing pressure-sensitive adhesive layer            providing the area of release ranging from about 6 cm² to            about 19 cm².            57. Transdermal therapeutic system in accordance with item            56, the size of said buprenorphine-containing            pressure-sensitive adhesive layer providing the area of            release ranging from about 6 cm² to about 18 cm².            58. Transdermal therapeutic system in accordance with item            56, the size of said buprenorphine-containing            pressure-sensitive adhesive layer providing the area of            release ranging from about 10 cm² to about 16 cm².            59. Transdermal therapeutic system in accordance with any            one of items 16, 21, 26, or 53 to 58, said transdermal            therapeutic system providing a mean AUCt of more than 28,000            pg·hr/ml over about 168 hours of administration after a            single-dose administration to a subject population.            60. Transdermal therapeutic system in accordance with item            59, said transdermal therapeutic system providing a mean            AUCt of more than 32,000 pg·hr/ml over about 168 hours of            administration after a single-dose administration to a            subject population.            61. Transdermal therapeutic system in accordance with item            59, said transdermal therapeutic system providing a mean            AUCt of from more than 32,000 pg·hr/ml to about 64,000            pg·hr/ml over about 168 hours of administration after a            single-dose administration to a subject population.            62. Transdermal therapeutic system in accordance with any            one of items 16, 21, 26, or 53 to 61, wherein the            transdermal therapeutic system provides a nominal mean            release rate of about 20 μg/hr over about 168 hours of            administration.            63. Transdermal therapeutic system in accordance with any            one of items 16, 21, 26, or 53 to 61, wherein the            transdermal therapeutic system provides a mean release rate            ranging from about 15 to about 25 μg/hr over about 168 hours            of administration.            64. Transdermal therapeutic system in accordance with any            one of items 16, 21, 26, or 53 to 63, wherein buprenorphine            is present in the form of buprenorphine base and wherein the            transdermal therapeutic system when tested in a comparative            clinical study is bioequivalent to the commercial product            BuTrans® having an area of release of 25 cm².            65. Transdermal therapeutic system in accordance with any            one of items 1 to 7, the amount of said buprenorphine            contained in the transdermal therapeutic system ranging from            about 11.5 mg to about 24 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof.            66. Transdermal therapeutic system in accordance with item            65, the amount of said buprenorphine contained in the            transdermal therapeutic system ranging from about 11.5 mg to            about 21 mg buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            67. Transdermal therapeutic system in accordance with item            65, the amount of said buprenorphine contained in the            transdermal therapeutic system ranging from about 11.5 mg to            about 14 mg buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            68. Transdermal therapeutic system in accordance with any            one of items 65 to 67, the size of said            buprenorphine-containing pressure-sensitive adhesive layer            providing the area of release ranging from about 12 cm² to            about 28.5 cm².            69. Transdermal therapeutic system in accordance with item            68, the size of said buprenorphine-containing            pressure-sensitive adhesive layer providing the area of            release ranging from about 12 cm² to about 27 cm².            70. Transdermal therapeutic system in accordance with item            68, the size of said buprenorphine-containing            pressure-sensitive adhesive layer providing the area of            release ranging from about 17 cm² to about 23 cm²,            71. Transdermal therapeutic system in accordance with any            one of items 17, 22, 27, or 65 to 70, said transdermal            therapeutic system providing a mean AUCt of more than 42,000            pg·hr/ml over about 168 hours of administration after a            single-dose administration to a subject population.            72. Transdermal therapeutic system in accordance with item            71, said transdermal therapeutic system providing a mean            AUCt of more than 48,000 pg·hr/ml over about 168 hours of            administration after a single-dose administration to a            subject population.            73. Transdermal therapeutic system in accordance with item            71, said transdermal therapeutic system providing a mean            AUCt of from more than 48,000 pg·hr/ml to about 96,000            pg·hr/ml over about 168 hours of administration after a            single-dose administration to a subject population.            74. Transdermal therapeutic system in accordance with any            one of items 17, 22, 27, or 65 to 73, wherein the            transdermal therapeutic system provides a nominal mean            release rate of about 30 gμg/hr over about 168 hours of            administration.            75. Transdermal therapeutic system in accordance with any            one of items 17, 22, 27, or 65 to 73, wherein the            transdermal therapeutic system provides a mean release rate            ranging from about 26 to about 35 μg/hr over about 168 hours            of administration.            76. Transdermal therapeutic system in accordance with any            one of items 1 to 7, the amount of said buprenorphine            contained in the transdermal therapeutic system ranging from            about 15 mg to about 32 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof.            77. Transdermal therapeutic system in accordance with item            76, the amount of said buprenorphine contained in the            transdermal therapeutic system ranging from about 15 mg to            about 28 mg buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            78. Transdermal therapeutic system in accordance with item            76, the amount of said buprenorphine contained in the            transdermal therapeutic system ranging from about 15 mg to            about 24 mg buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            79. Transdermal therapeutic system in accordance with any            one of items 76 to 78, the size of said            buprenorphine-containing pressure-sensitive adhesive layer            providing the area of release ranging from about 16 cm² to            about 38 cm².            80. Transdermal therapeutic system in accordance with item            79, the size of said buprenorphine-containing            pressure-sensitive adhesive layer providing the area of            release ranging from about 16 cm² to about 35 cm².            81. Transdermal therapeutic system in accordance with item            79, the size of said buprenorphine-containing            pressure-sensitive adhesive layer providing the area of            release ranging from about 23.5 cm² to about 32 cm².            82. Transdermal therapeutic system in accordance with any            one of items 18, 23, 28, or 76 to 81, said transdermal            therapeutic system providing a mean AUCt of more than 62,000            pg·hr/ml over about 168 hours of administration after a            single-dose administration to a subject population.            83. Transdermal therapeutic system in accordance with item            82, said transdermal therapeutic system providing a mean            AUCt of more than 64,000 pg·hr/ml over about 168 hours of            administration after a single-dose administration to a            subject population.            84. Transdermal therapeutic system in accordance with item            82, said transdermal therapeutic system providing a mean            AUCt of from more than 64,000 pg·hr/ml to about 128,000            pg·hr/ml over about 168 hours of administration after a            single-dose administration to a subject population.            85. Transdermal therapeutic system in accordance with any            one of items 18, 23, 28, or 76 to 84, wherein the            transdermal therapeutic system provides a nominal mean            release rate of about 40 μg/hr over about 168 hours of            administration.            86. Transdermal therapeutic system in accordance with any            one of items 18, 23, 28, or 76 to 84, wherein the            transdermal therapeutic system provides a mean release rate            ranging from about 36 to about 45 μg/hr over about 168 hours            of administration.            87. Transdermal therapeutic system in accordance with any            one of items 1 to 86, said transdermal therapeutic system            providing an arithmetic mean tmax of from about 60 hr to            about 120 hr after a single-dose administration to a subject            population.            88. Transdermal therapeutic system in accordance with item            87, said transdermal therapeutic system providing an            arithmetic mean tmax of from about 66 hr to less than 108 hr            after a single-dose administration to a subject population.            89. Transdermal therapeutic system in accordance with item            87, said transdermal therapeutic system providing an            arithmetic mean tmax of from about 72 hr to about 96 hr            after a single-dose administration to a subject population.            90. Transdermal therapeutic system in accordance with any            one of items 1 to 89, said transdermal therapeutic system            providing a mean AUCt per area of release of more than 1,700            pg·hr/ml-cm² over about 168 hours of administration after a            single-dose administration to a subject population.            91. Transdermal therapeutic system in accordance with item            90, said transdermal therapeutic system providing a mean            AUCt per area of release of more than 1,900 pg·hr/ml-cm²            over about 168 hours of administration after a single-dose            administration to a subject population.            92. Transdermal therapeutic system in accordance with item            90, said transdermal therapeutic system providing a mean            AUCt per area of release of more than 2,300 pg·hr/ml-cm²            over about 168 hours of administration after a single-dose            administration to a subject population.            93. Transdermal therapeutic system in accordance with any            one of items 1 to 92, said buprenorphine-containing            pressure-sensitive adhesive layer containing more than 0.55            mg/cm² of buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            94. Transdermal therapeutic system in accordance with item            93, said buprenorphine-containing pressure-sensitive            adhesive layer containing more than 0.6 mg/cm² of            buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            95. Transdermal therapeutic system in accordance with item            93, said buprenorphine-containing pressure-sensitive            adhesive layer containing more than 0.7 mg/cm² of            buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            96. Transdermal therapeutic system in accordance with item            93, said buprenorphine-containing pressure-sensitive            adhesive layer containing more than 0.8 mg/cm² of            buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            97. Transdermal therapeutic system in accordance with item            93, said buprenorphine-containing pressure-sensitive            adhesive layer containing more than 0.9 mg/cm² of            buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            98. Transdermal therapeutic system in accordance with item            93, said buprenorphine-containing pressure-sensitive            adhesive layer containing more than 1 mg/cm² of            buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            99. Transdermal therapeutic system in accordance with item            93, said buprenorphine-containing pressure-sensitive            adhesive layer containing more than 1.1 mg/cm² of            buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            100. Transdermal therapeutic system in accordance with any            one of items 1 to 92, said buprenorphine-containing            pressure-sensitive adhesive layer containing from about 0.55            mg/cm² to about 2 mg/cm² or from about 0.6 mg/cm² to about 2            mg/cm²of buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            101. Transdermal therapeutic system in accordance with item            100, said buprenorphine-containing pressure-sensitive            adhesive layer containing from about 0.7 mg/cm² to about 2            mg/cm² of buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            102. Transdermal therapeutic system in accordance with item            100, said buprenorphine-containing pressure-sensitive            adhesive layer containing from about 0.8 mg/cm² to about 2            mg/cm² of buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            103. Transdermal therapeutic system in accordance with item            100, said buprenorphine-containing pressure-sensitive            adhesive layer containing from about 0.9 mg/cm² to about 2            mg/cm² of buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            104. Transdermal therapeutic system in accordance with item            100, said buprenorphine-containing pressure-sensitive            adhesive layer containing from about 1 mg/cm² to about 2            mg/cm² of buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            105. Transdermal therapeutic system in accordance with item            100, said buprenorphine-containing pressure-sensitive            adhesive layer containing from about 1.1 mg/cm² to about 2            mg/cm² of buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            106. Transdermal therapeutic system in accordance with any            one of items 1 to 105, said buprenorphine-containing            pressure-sensitive adhesive layer containing more than 5%            buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            107. Transdermal therapeutic system in accordance with item            106, said buprenorphine-containing pressure-sensitive            adhesive layer containing more than 6% buprenorphine base or            an equimolar amount of a pharmaceutically acceptable salt            thereof.            108. Transdermal therapeutic system in accordance with item            106, said buprenorphine-containing pressure-sensitive            adhesive layer containing more than 7% buprenorphine base or            an equimolar amount of a pharmaceutically acceptable salt            thereof.            109. Transdermal therapeutic system in accordance with item            106, said buprenorphine-containing pressure-sensitive            adhesive layer containing more than 8% buprenorphine base or            an equimolar amount of a pharmaceutically acceptable salt            thereof.            110. Transdermal therapeutic system in accordance with item            106, said buprenorphine-containing pressure-sensitive            adhesive layer containing more than 9% buprenorphine base or            an equimolar amount of a pharmaceutically acceptable salt            thereof.            111. Transdermal therapeutic system in accordance with any            one of items 1 to 105, said buprenorphine-containing            pressure-sensitive adhesive layer containing from about 6%            to about 20% buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            112. Transdermal therapeutic system in accordance with item            111, said buprenorphine-containing pressure-sensitive            adhesive layer containing from about 7% to about 20%            buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            113. Transdermal therapeutic system in accordance with item            111, said buprenorphine-containing pressure-sensitive            adhesive layer containing from about 8% to about 20%            buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            114. Transdermal therapeutic system in accordance with item            111, said buprenorphine-containing pressure-sensitive            adhesive layer containing from more than 9% to about 20%            buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            115. Transdermal therapeutic system in accordance with any            one of items 1 to 114, the buprenorphine-containing            pressure-sensitive adhesive layer being coated at a dry            weight of more than 6 mg/cm².            116. Transdermal therapeutic system in accordance with item            115, the buprenorphine-containing pressure-sensitive            adhesive layer being coated at a dry weight of more than 8            mg/cm².            117. Transdermal therapeutic system in accordance with item            115, the buprenorphine-containing pressure-sensitive            adhesive layer being coated at a dry weight of more than 10            mg/cm².            118. Transdermal therapeutic system in accordance with any            one of items 1 to 114, the buprenorphine-containing            pressure-sensitive adhesive layer being coated at a dry            weight ranging from 6 mg/cm² to about 14 mg/cm².            119. Transdermal therapeutic system in accordance with item            118, the buprenorphine-containing pressure-sensitive            adhesive layer being coated at a dry weight ranging from 8            mg/cm² to about 14 mg/cm².            120. Transdermal therapeutic system in accordance with item            118, the buprenorphine-containing pressure-sensitive            adhesive layer being coated at a dry weight ranging from 10            mg/cm² to about 13 mg/cm².            121. Transdermal therapeutic system in accordance with item            118, the buprenorphine-containing pressure-sensitive            adhesive layer being coated at a dry weight ranging from            11.5 mg/cm² to about 12.5 mg/cm².            122. Transdermal therapeutic system in accordance with any            one of items 1 to 121, wherein the carboxylic acid is            levulinic acid, said buprenorphine-containing            pressure-sensitive adhesive layer containing the same %            amounts of levulinic acid and buprenorphine, based on the %            amount of buprenorphine base.            123. Transdermal therapeutic system in accordance with any            one of items 1 to 121, wherein the carboxylic acid is            levulinic acid, said buprenorphine-containing            pressure-sensitive adhesive layer containing less % amounts            of levulinic acid than % amounts of buprenorphine, based on            the % amount of buprenorphine base.            124. Transdermal therapeutic system in accordance with any            one of items 1 to 123, wherein the carboxylic acid is            levulinic acid, said buprenorphine-containing            pressure-sensitive adhesive layer containing more than 5%            levulinic acid.            125. Transdermal therapeutic system in accordance with item            124, said buprenorphine-containing pressure-sensitive            adhesive layer containing more than 6% levulinic acid.            126. Transdermal therapeutic system in accordance with item            124, said buprenorphine-containing pressure-sensitive            adhesive layer containing more than 7% levulinic acid.            127. Transdermal therapeutic system in accordance with item            124, said buprenorphine-containing pressure-sensitive            adhesive layer containing more than 8% levulinic acid.            128. Transdermal therapeutic system in accordance with item            124, said buprenorphine-containing pressure-sensitive            adhesive layer containing more than 9% levulinic acid.            129. Transdermal therapeutic system in accordance with any            one of items 1 to 78, wherein the carboxylic acid is            levulinic acid, said buprenorphine-containing            pressure-sensitive adhesive layer containing from about 6%            to about 20% levulinic acid.            130. Transdermal therapeutic system in accordance with item            129, said buprenorphine-containing pressure-sensitive            adhesive layer containing from about 7% to about 20%            levulinic acid.            131. Transdermal therapeutic system in accordance with item            129, said buprenorphine-containing pressure-sensitive            adhesive layer containing from about 6% to about 9%            levulinic acid.            132. Transdermal therapeutic system in accordance with item            129, said buprenorphine-containing pressure-sensitive            adhesive layer containing from more than 9% to about 15%            levulinic acid.            133. Transdermal therapeutic system in accordance with item            129, said buprenorphine-containing pressure-sensitive            adhesive layer containing from more than 9% to about 15%            buprenorphine base and form about 6% to about 9% levulinic            acid.            134. Transdermal therapeutic system in accordance with item            129, said buprenorphine-containing pressure-sensitive            adhesive layer containing from more than 9% to about 15%            buprenorphine base and from more than 9% to about 15%            levulinic acid.            135. Transdermal therapeutic system in accordance with any            one of items 1 to 134, the pressure-sensitive adhesive layer            being coated at a dry weight of about 12 mg/cm², and wherein            said buprenorphine is present in the form of buprenorphine            base and the dry pressure-sensitive adhesive layer contains            about 10% buprenorphine base, and wherein the carboxylic            acid is levulinic acid the dry pressure-sensitive adhesive            layer contains about 7% levulinic acid.            136. Transdermal therapeutic system in accordance with any            one of items 1 to 134, the pressure-sensitive adhesive layer            being coated at a dry weight of about 12 mg/cm², and wherein            said buprenorphine is present in the form of buprenorphine            base and the dry pressure-sensitive adhesive layer contains            about 10% buprenorphine base, and wherein the carboxylic            acid is levulinic acid the dry pressure-sensitive adhesive            layer contains about 10% levulinic acid.            137. A set of five different transdermal therapeutic systems            in accordance with any one of items 1 to 136, wherein            the first transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 1.5            cm² to about 5.5 cm² and contains an amount of said            buprenorphine from about 1 mg to about 4.5 mg buprenorphine            base or an equimolar amount of a pharmaceutically acceptable            salt thereof;            the second transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 3 cm²            to about 9 cm² and contains an amount of said buprenorphine            from about 4 mg to about 9 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof; and            the third transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 6 cm²            to about 14 cm² and contains an amount of said buprenorphine            from about 8 mg to about 14 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof; and            the fourth transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 13            cm² to about 17 cm² and contains an amount of said            buprenorphine from about 15 mg to about 20 mg buprenorphine            base or an equimolar amount of a pharmaceutically acceptable            salt thereof; and            the fifth transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 16            cm² to about 24 cm² and contains an amount of said            buprenorphine from about 20 mg to about 28 mg buprenorphine            base or an equimolar amount of a pharmaceutically acceptable            salt thereof.            138. A set of five different transdermal therapeutic systems            in accordance with any one of items 1 to 136, wherein            the first transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 2 cm²            to about 4 cm² and contains an amount of said buprenorphine            from about 2 mg to about 4 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof;            the second transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 4.5            cm² to about 7.5 cm² and contains an amount of said            buprenorphine from about 5 mg to about 8 mg buprenorphine            base or an equimolar amount of a pharmaceutically acceptable            salt thereof; and            the third transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 8 cm²            to about 12 cm² and contains an amount of said buprenorphine            from about 10 mg to about 14 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof; and            the fourth transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 13            cm² to about 16 cm² and contains an amount of said            buprenorphine from about 16 mg to about 19 mg buprenorphine            base or an equimolar amount of a pharmaceutically acceptable            salt thereof; and            the fifth transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 17            cm² to about 22 cm² and contains an amount of said            buprenorphine from about 21 mg to about 26 mg buprenorphine            base or an equimolar amount of a pharmaceutically acceptable            salt thereof.            139. A set of five different transdermal therapeutic systems            in accordance with any one of items 1 to 136, wherein            the first transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 2 cm²            to about 3 cm² and contains an amount of said buprenorphine            from about 2.5 mg to about 4 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof;            the second transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 4.5            cm² to about 6 cm² and contains an amount of said            buprenorphine from about 5 mg to about 7 mg buprenorphine            base or an equimolar amount of a pharmaceutically acceptable            salt thereof; and            the third transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 9 cm²            to about 11 cm² and contains an amount of said buprenorphine            from about 11 mg to about 13 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof; and            the fourth transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 14            cm² to about 16 cm² and contains an amount of said            buprenorphine from about 17 mg to about 19 mg buprenorphine            base or an equimolar amount of a pharmaceutically acceptable            salt thereof; and            the fifth transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 18            cm² to about 21 cm² and contains an amount of said            buprenorphine from about 22 mg to about 25 mg buprenorphine            base or an equimolar amount of a pharmaceutically acceptable            salt thereof.            140. Transdermal therapeutic system in accordance with any            one of items 1 to 139, said buprenorphine-containing            self-adhesive layer structure being attached to a second            larger active agent-free self-adhesive layer structure for            enhancing the adhesive properties of the overall transdermal            therapeutic system.            141. Transdermal therapeutic system in accordance with item            140, said second active-free self-adhesive layer structure            comprising a backing layer and an active agent-free            pressure-sensitive adhesive layer of pressure-sensitive            adhesive based on polyacrylates.            142. Transdermal therapeutic system in accordance with item            140, said second active-free self-adhesive layer structure            comprising a backing layer and an active agent-free            pressure-sensitive adhesive layer of pressure-sensitive            adhesive based on polysiloxane.            143. Transdermal therapeutic system in accordance with any            one of items 1 to 140, said polymer-based pressure-sensitive            adhesive is based on polysiloxane in the            buprenorphine-containing pressure-sensitive adhesive layer            and/or in the active agent-free pressure-sensitive adhesive            layer being amine-resistant.            144. Transdermal therapeutic system in accordance with any            one of items 1 to 143, wherein the polymer-based            pressure-sensitive adhesive is based on polysiloxane and the            polysiloxane is amine-resistant being a product of the            condensation reaction of silanol endblocked            polydimethylsiloxane with a silica resin and the residual            silanol functionality being capped with trimethylsiloxy            groups.            145. Transdermal therapeutic system in accordance with            anyone of items 1 to 144, wherein the polymer-based            pressure-sensitive adhesive is based on polysiloxane and            wherein for the production of the buprenorphine-containing            and the active agent-free pressure-sensitive adhesive layer            an adhesive composition of the pressure-sensitive adhesive            based on polysiloxane in heptane is used.            146. Transdermal therapeutic system in accordance with any            one of items 1 to 145, wherein the polymer-based            pressure-sensitive adhesive is based on polysiloxane and is            characterized by a solution viscosity at 25° C. and 60%            solids content in heptane of more than about 150 mPa s.            147. Transdermal therapeutic system in accordance with item            146, the polymer-based pressure-sensitive adhesive is based            on polysiloxane and is characterized by a solution viscosity            at 25° C. 60% solids content in heptane of from about 200            mPa s to about 700 mPa s.            148. Transdermal therapeutic system in accordance with item            146, the polymer-based pressure-sensitive adhesive is based            on polysiloxane and is characterized by a solution viscosity            at 25° C. and 60% solids content in heptane of from about            350 mPa s to about 600 mPa s.            149. Transdermal therapeutic system in accordance with item            146, wherein the polymer-based pressure-sensitive adhesive            is based on polysiloxane and is characterized by a solution            viscosity at 25° C. and 60% solids content in heptane of            from 480 mPa s to about 550 mPa s or alternatively from            about 400 to less than 480 mPa s.            150. Transdermal therapeutic system in accordance items 146,            wherein the polymer-based pressure-sensitive adhesive is            based on polysiloxane is characterized by a solution            viscosity at 25° C. and 60% solids content in heptane of            about 500 mPa s or alternatively of about 450 mPa s.            151. Transdermal therapeutic system in accordance with any            one of items 1 to 150, the polymer-based pressure-sensitive            adhesive in the buprenorphine-containing layer and in the            active agent-free layer being an amine-resistant            pressure-sensitive adhesive based on polysiloxane and the            polysiloxane being a product of the condensation reaction of            silanol endblocked polydimethylsiloxane with a silica resin            and the residual silanol functionality being capped with            trimethylsiloxy groups and characterized by a solution            viscosity at 25° C. and 60% solids content in heptane of            more than 400 mPa s, and the buprenorphine-containing            pressure-sensitive adhesive layer being coated at a coating            dry weight of about 12 mg/cm² and containing about 10%            buprenorphine base and about 10% levulinic acid.            152. Transdermal therapeutic system in accordance with any            one of items 1 to 151, wherein buprenorphine is present in            the form of buprenorphine base and providing a mean            cumulative skin permeation rate measured in a Franz            diffusion cell with dermatomed human skin of more than 1.3            μg/cm²-hr over a 168 hours test.            153. Transdermal therapeutic system in accordance with item            152, providing a mean cumulative skin permeation rate            measured in a Franz diffusion cell with dermatomed human            skin of more than 1.5 μg/cm²-hr over a 168 hours test.            154. Transdermal therapeutic system in accordance with item            152, providing a mean cumulative skin permeation rate            measured in a Franz diffusion cell with dermatomed human            skin of more than 1.7 μg/cm²-hr over a 168 hours test.            155. Transdermal therapeutic system in accordance with item            152, providing a mean cumulative skin permeation rate            measured in a Franz diffusion cell with dermatomed human            skin of more than 2 μg/cm²-hr over a 168 hours test.            156. Transdermal therapeutic system in accordance with item            152, providing a mean cumulative skin permeation rate            measured in a Franz diffusion cell with dermatomed human            skin of more than 2.5 μg/cm²-hr over a 168 hours test.            157. Transdermal therapeutic system in accordance with item            152, providing a mean cumulative skin permeation rate            measured in a Franz diffusion cell with dermatomed human            skin of more than 3 μg/cm²-hr over a 168 hours test.            158. Transdermal therapeutic system in accordance with any            one of items 1 to 151, wherein buprenorphine is present in            the form of buprenorphine base and providing a mean            cumulative skin permeation rate measured in a Franz            diffusion cell with dermatomed human skin from about 1.3            μg/cm²-hr to about 4 μg/cm²-hr over a 168 hours test.            159. Transdermal therapeutic system in accordance with item            158, providing a mean cumulative skin permeation rate            measured in a Franz diffusion cell with dermatomed human            skin from about 1.7 μg/cm²-hr to about 4 μg/cm²-hr over a            168 hours test.            160. Transdermal therapeutic system in accordance with item            158, providing a mean cumulative skin permeation rate            measured in a Franz diffusion cell with dermatomed human            skin from about 2 μg/cm²-hr to about 4 μg/cm²-hr over a 168            hours test.            161. Transdermal therapeutic system in accordance with item            158, providing a mean cumulative skin permeation rate            measured in a Franz diffusion cell with dermatomed human            skin from about 2.5 μg/cm²-hr to about 4 μg/cm²-hr over a            168 hours test.            162. Transdermal therapeutic system in accordance with item            158, providing a mean cumulative skin permeation rate            measured in a Franz diffusion cell with dermatomed human            skin from about 3 μg/cm²-hr to about 4 μg/cm²-hr over a 168            hours test.            163. Transdermal therapeutic system in accordance with any            one of items 1 to 162, wherein buprenorphine is present in            the form of buprenorphine base and providing a cumulative            release of buprenorphine base as measured in a Franz            diffusion cell with dermatomed human skin of 220 μg/cm² to            640 μg/cm² over a time period of 168 hours.            164. Transdermal therapeutic system in accordance with item            163, providing a cumulative release of buprenorphine base as            measured in a Franz diffusion cell with dermatomed human            skin of 390 μg/cm² to 640 μg/cm² over a time period of 168            hours.            165. Transdermal therapeutic system in accordance with item            163, providing a cumulative release of buprenorphine base as            measured in a Franz diffusion cell with dermatomed human            skin of about 400 μg/cm² to about 640 μg/cm² over a time            period of 168 hours.            166. Transdermal therapeutic system in accordance with item            163, providing a cumulative release of buprenorphine base as            measured in a Franz diffusion cell with dermatomed human            skin of about 450 μg/cm² to about 640 μg/cm² over a time            period of 168 hours. 167. Transdermal therapeutic system in            accordance with item 163, providing a cumulative release of            buprenorphine base as measured in a Franz diffusion cell            with dermatomed human skin of about 500 μg/cm² to about 640            μg/cm² over a time period of 168 hours.            168. Transdermal therapeutic system in accordance with item            163, providing a cumulative release of buprenorphine base as            measured in a Franz diffusion cell with dermatomed human            skin of about 600 μg/cm² to about 640 μg/cm² over a time            period of 168 hours.            169. Transdermal therapeutic system in accordance with any            one of items 1 to 168, wherein buprenorphine is present in            the form of buprenorphine base and providing a            non-cumulative release of buprenorphine base as measured in            a Franz diffusion cell with dermatomed human skin of            2 μg/cm² to 10 μg/cm² in the first 8 hours,            20 μg/cm² to 80 μg/cm² from hour 8 to hour 24,            20 μg/cm² to 80 μg/cm² from hour 24 to hour 32,            30 μg/cm² to 120 μg/cm² from hour 32 to hour 48,            40 μg/cm² to 150 μg/cm² from hour 48 to hour 72,            100 μg/cm² to 300 μg/cm² from hour 72 to hour 144, and            30 μg/cm² to 100 μg/cm² from hour 144 to hour 168.            170. Transdermal therapeutic system in accordance with item            169, wherein buprenorphine is present in the form of            buprenorphine base and providing a non-cumulative release of            buprenorphine base as measured in a Franz diffusion cell            with dermatomed human skin of            2 μg/cm² to 6 μg/cm² in the first 8 hours,            25 μg/cm² to 60 μg/cm² from hour 8 to hour 24,            25 μg/cm² to 60 μg/cm² from hour 24 to hour 32,            40 μg/cm² to 100 μg/cm² from hour 32 to hour 48,            50 μg/cm² to 140 μg/cm² from hour 48 to hour 72,            100 μg/cm² to 280 μg/cm² from hour 72 to hour 144, and            30 μg/cm² to 100 μg/cm² from hour 144 to hour 168.            171. Transdermal therapeutic system in accordance with item            169, wherein buprenorphine is present in the form of            buprenorphine base and providing a non-cumulative release of            buprenorphine base as measured in a Franz diffusion cell            with dermatomed human skin of            3 μg/cm² to 6 μg/cm² in the first 8 hours,            30 μg/cm² to 50 μg/cm² from hour 8 to hour 24,            30 μg/cm² to 50 μg/cm² from hour 24 to hour 32,            60 μg/cm² to 90 μg/cm² from hour 32 to hour 48,            100 μg/cm² to 130 Jμg/cm² from hour 48 to hour 72,            200 μg/cm² to 280 μg/cm² from hour 72 to hour 144, and            60 μg/cm² to 100 Jμg/cm² from hour 144 to hour 168.            172. A set of two to five different transdermal therapeutic            systems each in accordance with any one of items 1 to 171,            wherein            the first transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 1 cm²            to about 4.8 cm² and contains an amount of said            buprenorphine from about 1 mg to about 4 mg buprenorphine            base or an equimolar amount of a pharmaceutically acceptable            salt thereof;            the second transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 3 cm²            to about 9.5 cm² and contains an amount of said            buprenorphine from about 3.5 mg to about 8 mg buprenorphine            base or an equimolar amount of a pharmaceutically acceptable            salt thereof; and            the third transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 6 cm²            to about 19 cm² and contains an amount of said buprenorphine            from about 6.5 mg to about 16 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof; and            the fourth transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 12            cm² to about 28.5 cm² and contains an amount of said            buprenorphine from about 11.5 mg to about 24 mg            buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof; and            the fifth transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 16            cm² to about 38 cm² and contains an amount of said            buprenorphine from about 15 mg to about 32 mg buprenorphine            base or an equimolar amount of a pharmaceutically acceptable            salt thereof.            173. A set of two to five different transdermal therapeutic            systems each in accordance with any one of items 1 to 171,            wherein            the first transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 1 cm²            to about 4.5 cm² and contains an amount of said            buprenorphine from about 1 mg to about 3.5 mg buprenorphine            base or an equimolar amount of a pharmaceutically acceptable            salt thereof;            the second transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 3 cm²            to about 9 cm² and contains an amount of said buprenorphine            from about 3.5 mg to about 7 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof; and            the third transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 6 cm²            to about 18 cm² and contains an amount of said buprenorphine            from about 6.5 mg to about 14 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof; and            the fourth transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 12            cm² to about 27 cm² and contains an amount of said            buprenorphine from about 11.5 mg to about 21 mg            buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof; and            the fifth transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 16            cm² to about 35 cm² and contains an amount of said            buprenorphine from about 15 mg to about 28 mg buprenorphine            base or an equimolar amount of a pharmaceutically acceptable            salt thereof.            174. A set of two to five different transdermal therapeutic            systems each in accordance with any one of items 1 to 171,            wherein            the first transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 2.5            cm² to about 4 cm² and contains an amount of said            buprenorphine from about 1 mg to about 3 mg buprenorphine            base or an equimolar amount of a pharmaceutically acceptable            salt thereof;            the second transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 5 cm²            to about 8 cm² and contains an amount of said buprenorphine            from about 3.5 mg to about 6 mg buprenorphine base or an            equimolar amount of a pharmaceutically acceptable salt            thereof; and            the third transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 10            cm² to about 16 cm² and contains an amount of said            buprenorphine from about 6.5 mg to about 11 mg buprenorphine            base or an equimolar amount of a pharmaceutically acceptable            salt thereof; and            the fourth transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 17            cm² to about 23 cm² and contains an amount of said            buprenorphine from about 11.5 mg to about 14 mg            buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof; and            the fifth transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 23.5            cm² to about 32 cm² and contains an amount of said            buprenorphine from about 15 mg to about 24 mg buprenorphine            base or an equimolar amount of a pharmaceutically acceptable            salt thereof.            175. Transdermal therapeutic system selected from a set in            accordance with any one of items 172 to 174, wherein            buprenorphine is present in the form of buprenorphine base            and wherein            the first transdermal therapeutic system when tested in a            comparative clinical study is bioequivalent to a reference            product having an area of release of about 6.25 cm² and            providing a nominal mean release rate of about 5 μg/hr over            about 168 hours of administration,            the second transdermal therapeutic system when tested in a            comparative clinical study is bioequivalent to a reference            product having an area of release of about 12.5 cm² and            providing a nominal mean release rate of about 10 μg/hr over            about 168 hours of administration,            the third transdermal therapeutic system when tested in a            comparative clinical study is bioequivalent to a reference            product having an area of release of about 25 cm² and            providing a nominal mean release rate of about 20 μg/hr over            about 168 hours of administration,            the fourth transdermal therapeutic system when tested in a            comparative clinical study is bioequivalent to a reference            product having an area of release of about 37.5 cm² and            providing a nominal mean release rate of about 30 μg/hr over            about 168 hours of administration,            the fifth transdermal therapeutic system when tested in a            comparative clinical study is bioequivalent to a reference            product having an area of release of about 50 cm² and            providing a nominal mean release rate of about 40 μg/hr over            about 168 hours of administration,            wherein the reference product is prepared by the following            steps:    -   1. homogenizing of 1,139 g of a 47.83% polyacrylate solution of        a self-crosslinked acrylate copolymer of 2-ethylhexyl acrylate,        vinyl acetate, acrylic acid (solvent: ethyl        acetate:heptanes:isopropanol:toluene:acetylacetonate in the        ratio of 37:26:26:4:1), 100 g of levulinic acid, 150 g of oleyl        oleate, 100 g of polyvinylpyrrolidone, 150 g of ethanol, 200 g        of ethyl acetate, and 100 g of buprenorphine base to provide a        mixture;    -   2. stirring the mixture of step 1 for about 2 hours and        controlling the dissolution of all solids visually whereas        controlling the evaporation loss by reweighing and replenishing        the possible solvent loss by ethyl acetate;    -   3. subsequently applying the mixture on a transparent polyester        film in such a manner that the mass per unit area of the dry        adhesive layer amounts to about 80 g/m² wherein the polyester        film is rendered removable by means of siliconization and serves        as protective layer,    -   4. removing the solvents of the mixture applied on a transparent        polyester film in step 3 by drying with heated air which is led        over a moist lane resulting in evaporation of the solvents, but        also in melting of the levulinic acid and covering the adhesive        film with a polyester foil;    -   5. punching the area of release of 6.25 cm², 12.5 cm², 25 cm²,        37.5 cm² and 50 cm², respectively, by means of suitable cutting        tools and removing the edges left between the individual        systems.        176. Transdermal therapeutic system comprising buprenorphine for        the transdermal administration of buprenorphine selected from:        a first transdermal therapeutic system providing a size of the        area of release ranging from about 1 cm² to about 4.8 cm² and        containing an amount of said buprenorphine from 1 mg to about 4        mg buprenorphine base or an equimolar amount of a        pharmaceutically acceptable salt thereof and providing a mean        AUCt of more than 7,000 pg·hr/ml over about 168 hours of        administration after a single-dose administration to a subject        population;        a second transdermal therapeutic system providing a size of the        area of release ranging from about 3 cm² to about 9.5 cm² and        containing an amount of said buprenorphine from about 3.5 mg to        about 8 mg buprenorphine base or an equimolar amount of a        pharmaceutically acceptable salt thereof and providing a mean        AUCt of more than 14,000 pg·hr/ml over about 168 hours of        administration after a single-dose administration to a subject        population; and        a third transdermal therapeutic system providing a size of the        area of release ranging from about 6 cm² to about 19 cm² and        containing an amount of said buprenorphine from about 6.5 mg to        about 16 mg buprenorphine base or an equimolar amount of a        pharmaceutically acceptable salt thereof and providing a mean        AUCt of more than 28,000 pg·hr/ml over about 168 hours of        administration after a single-dose administration to a subject        population; and        a fourth transdermal therapeutic system providing a size of the        area of release ranging from about 12 cm² to about 28.5 cm² and        containing an amount of said buprenorphine from about 11.5 mg to        about 24 mg buprenorphine base or an equimolar amount of a        pharmaceutically acceptable salt thereof and providing a mean        AUCt of more than 42,000 pg·hr/ml over about 168 hours of        administration after a single-dose administration to a subject        population; and        a fifth transdermal therapeutic system providing a size of the        area of release ranging from about 16 cm² to about 38 cm² and        containing an amount of said buprenorphine from about 15 mg to        about 32 mg buprenorphine base or an equimolar amount of a        pharmaceutically acceptable salt thereof and providing a mean        AUCt of more than 62,000 pg·hr/ml over about 168 hours of        administration after a single-dose administration to a subject        population.        177. Transdermal therapeutic system in accordance with item 176,        wherein        the first transdermal therapeutic system contains an amount of        said buprenorphine ranging from about 1 mg to about 3.5 mg        buprenorphine base or an equimolar amount of a pharmaceutically        acceptable salt thereof and provides a size of the area of        release ranging from about 1 cm² to about 4.5 cm²; and        the second transdermal therapeutic system contains an amount of        said buprenorphine ranging from about 3.5 mg to about 7 mg        buprenorphine base or an equimolar amount of a pharmaceutically        acceptable salt thereof and provides a size of the area of        release ranging from about 3 cm² to about 9 cm²; and        the third transdermal therapeutic system contains an amount of        said buprenorphine ranging from about 6.5 mg to about 14 mg        buprenorphine base or an equimolar amount of a pharmaceutically        acceptable salt thereof and provides a size of the area of        release ranging from about 6 cm² to about 18 cm²; and        the fourth transdermal therapeutic system contains an amount of        said buprenorphine ranging from about 11.5 mg to about 21 mg        buprenorphine base or an equimolar amount of a pharmaceutically        acceptable salt thereof and provides a size of the area of        release ranging about 12 cm² to about 27 cm²; and        the fifth transdermal therapeutic system contains an amount of        said buprenorphine ranging from about 15 mg to about 28 mg        buprenorphine base or an equimolar amount of a pharmaceutically        acceptable salt thereof and provides a size of the area of        release ranging from about 16 cm² to about 35 cm².        178. Transdermal therapeutic system in accordance with item 176,        wherein        the first transdermal therapeutic system contains an amount of        said buprenorphine ranging from about 1 mg to about 3 mg        buprenorphine base or an equimolar amount of a pharmaceutically        acceptable salt thereof and provides a size of the area of        release ranging from about 2.5 cm² to about 4 cm²; and        the second transdermal therapeutic system contains an amount of        said buprenorphine ranging from about 3.5 mg to about 6 mg        buprenorphine base or an equimolar amount of a pharmaceutically        acceptable salt thereof and provides a size of the area of        release ranging from about 5 cm² to about 8 cm²; and        the third transdermal therapeutic system contains an amount of        said buprenorphine ranging from about 6.5 mg to about 11 mg        buprenorphine base or an equimolar amount of a pharmaceutically        acceptable salt thereof and provides a size of the area of        release ranging from about 10 cm² to about 16 cm²; and        the fourth transdermal therapeutic system contains an amount of        said buprenorphine ranging from about 11.5 mg to about 14 mg        buprenorphine base or an equimolar amount of a pharmaceutically        acceptable salt thereof and provides a size of the area of        release ranging about 17 cm² to about 23 cm²; and        the fifth transdermal therapeutic system contains an amount of        said buprenorphine ranging from about 15 mg to about 24 mg        buprenorphine base or an equimolar amount of a pharmaceutically        acceptable salt thereof and provides a size of the area of        release ranging from about 23.5 cm² to about 32 cm².        179. Transdermal therapeutic system in accordance with any one        of items 176 to 178, wherein        the first transdermal therapeutic system provides a mean AUCt of        more than 8,000 pg·hr/ml over about 168 hours of administration        after a single-dose administration to a subject population; and        the second transdermal therapeutic system provides a mean AUCt        of more than 16,000 pg·hr/ml over about 168 hours of        administration after a single-dose administration to a subject        population; and        the third transdermal therapeutic system provides a mean AUCt of        more than 32,000 pg·hr/ml over about 168 hours of administration        after a single-dose administration to a subject population; and        the fourth transdermal therapeutic system provides a mean AUCt        of more than 48,000 pg·hr/ml over about 168 hours of        administration after a single-dose administration to a subject        population; and        the fifth transdermal therapeutic system provides a mean AUCt of        more than 64,000 pg·hr/ml over about 168 hours of administration        after a single-dose administration to a subject population.        180. Transdermal therapeutic system comprising buprenorphine for        the transdermal administration of buprenorphine selected from:        a first transdermal therapeutic system providing a size of the        area of release ranging from about 1 cm² to about 4.8 cm² and        containing an amount of said buprenorphine from 1 mg to about 4        mg buprenorphine base or an equimolar amount of a        pharmaceutically acceptable salt thereof and providing a nominal        mean release rate of about 5 μg/hr over about 168 hours of        administration;        a second transdermal therapeutic system providing a size of the        area of release ranging from about 3 cm² to about 9.5 cm² and        containing an amount of said buprenorphine from about 3.5 mg to        about 8 mg buprenorphine base or an equimolar amount of a        pharmaceutically acceptable salt thereof and providing a nominal        mean release rate of about 10 μg/hr over about 168 hours of        administration; and        a third transdermal therapeutic system providing a size of the        area of release ranging from about 6 cm² to about 19 cm² and        containing an amount of said buprenorphine from about 6.5 mg to        about 16 mg buprenorphine base or an equimolar amount of a        pharmaceutically acceptable salt thereof and providing a nominal        mean release rate of about 20 μg/hr over about 168 hours of        administration; and        a fourth transdermal therapeutic system providing a size of the        area of release ranging from about 12 cm² to about 28.5 cm² and        containing an amount of said buprenorphine from about 11.5 mg to        about 24 mg buprenorphine base or an equimolar amount of a        pharmaceutically acceptable salt thereof and providing a nominal        mean release rate of about 30 μg/hr over about 168 hours of        administration; and        a fifth transdermal therapeutic system providing a size of the        area of release ranging from about 16 cm² to about 38 cm² and        containing an amount of said buprenorphine from about 15 mg to        about 32 mg buprenorphine base or an equimolar amount of a        pharmaceutically acceptable salt thereof and providing a nominal        mean release rate of about 40 μg/hr over about 168 hours of        administration.        181. Transdermal therapeutic system in accordance with item 180,        wherein the first transdermal therapeutic system contains an        amount of said buprenorphine ranging from about 1 mg to about        3.5 mg buprenorphine base or an equimolar amount of a        pharmaceutically acceptable salt thereof and provides a size of        the area of release ranging from about 1 cm² to about 4.5 cm²;        and        the second transdermal therapeutic system contains an amount of        said buprenorphine ranging from about 3.5 mg to about 7 mg        buprenorphine base or an equimolar amount of a pharmaceutically        acceptable salt thereof and provides a size of the area of        release ranging from about 3 cm² to about 9 cm²; and        the third transdermal therapeutic system contains an amount of        said buprenorphine ranging from about 6.5 mg to about 14 mg        buprenorphine base or an equimolar amount of a pharmaceutically        acceptable salt thereof and provides a size of the area of        release ranging from about 6 cm² to about 18 cm²; and        the fourth transdermal therapeutic system contains an amount of        said buprenorphine ranging from about 11.5 mg to about 21 mg        buprenorphine base or an equimolar amount of a pharmaceutically        acceptable salt thereof and provides a size of the area of        release ranging about 12 cm² to about 27 cm²; and        the fifth transdermal therapeutic system contains an amount of        said buprenorphine ranging from about 15 mg to about 28 mg        buprenorphine base or an equimolar amount of a pharmaceutically        acceptable salt thereof and provides a size of the area of        release ranging from about 16 cm² to about 35 cm².        182. Transdermal therapeutic system in accordance with item 180,        wherein        the first transdermal therapeutic system contains an amount of        said buprenorphine ranging from about 1 mg to about 3 mg        buprenorphine base or an equimolar amount of a pharmaceutically        acceptable salt thereof and provides a size of the area of        release ranging from about 2.5 cm² to about 4 cm²; and        the second transdermal therapeutic system contains an amount of        said buprenorphine ranging from about 3.5 mg to about 6 mg        buprenorphine base or an equimolar amount of a pharmaceutically        acceptable salt thereof and provides a size of the area of        release ranging from about 5 cm² to about 8 cm²; and        the third transdermal therapeutic system contains an amount of        said buprenorphine ranging from about 6.5 mg to about 11 mg        buprenorphine base or an equimolar amount of a pharmaceutically        acceptable salt thereof and provides a size of the area of        release ranging from about 10 cm² to about 16 cm²; and        the fourth transdermal therapeutic system contains an amount of        said buprenorphine ranging from about 11.5 mg to about 14 mg        buprenorphine base or an equimolar amount of a pharmaceutically        acceptable salt thereof and provides a size of the area of        release ranging about 17 cm² to about 23 cm²; and        the fifth transdermal therapeutic system contains an amount of        said buprenorphine ranging from about 15 mg to about 24 mg        buprenorphine base or an equimolar amount of a pharmaceutically        acceptable salt thereof and provides a size of the area of        release ranging from about 23.5 cm² to about 32 cm².        183. Transdermal therapeutic system in accordance with any one        of items 176 to 182, wherein buprenorphine is present in the        form of buprenorphine base and providing a non-cumulative        release of buprenorphine base as measured in a Franz diffusion        cell with dermatomed human skin of        2 μg/cm² to 10 μg/cm² in the first 8 hours,        20 μg/cm² to 80 μg/cm² from hour 8 to hour 24,        20 μg/cm² to 80 μg/cm² from hour 24 to hour 32,        30 μg/cm² to 120 μg/cm² from hour 32 to hour 48,        40 μg/cm² to 150 μg/cm² from hour 48 to hour 72,        100 μg/cm² to 300 μg/cm² from hour 72 to hour 144, and        30 μg/cm² to 100 μg/cm² from hour 144 to hour 168.        184. Transdermal therapeutic system in accordance with item 183,        wherein buprenorphine is present in the form of buprenorphine        base and providing a non-cumulative release of buprenorphine        base as measured in a Franz diffusion cell with dermatomed human        skin of        2 μg/cm² to 6 μg/cm² in the first 8 hours,        25 μg/cm² to 60 μg/cm² from hour 8 to hour 24,        25 μg/cm² to 60 μg/cm² from hour 24 to hour 32,        40 μg/cm² to 100 μg/cm² from hour 32 to hour 48,        50 μg/cm² to 140 μg/cm² from hour 48 to hour 72,        100 μg/cm² to 280 μg/cm² from hour 72 to hour 144, and        30 μg/cm² to 100 μg/cm² from hour 144 to hour 168.        185. Transdermal therapeutic system in accordance with item 183,        wherein buprenorphine is present in the form of buprenorphine        base and providing a non-cumulative release of buprenorphine        base as measured in a Franz diffusion cell with dermatomed human        skin of        3 μg/cm² to 6 μg/cm² in the first 8 hours,        30 μg/cm² to 50 μg/cm² from hour 8 to hour 24,        30 μg/cm² to 50 μg/cm² from hour 24 to hour 32,        60 μg/cm² to 90 μg/cm² from hour 32 to hour 48,        100 μg/cm² to 130 μg/cm² from hour 48 to hour 72,        200 μg/cm² to 280 μg/cm² from hour 72 to hour 144, and        60 μg/cm² to 100 μg/cm² from hour 144 to hour 168.        186. A set of transdermal therapeutic systems including at least        two transdermal therapeutic systems selected from the first,        second, third, fourth and fifth transdermal therapeutic system        in accordance with any one of items 176 to 185.        187. Transdermal therapeutic system comprising buprenorphine for        the transdermal administration of buprenorphine, wherein        buprenorphine is present in the form of buprenorphine base and        providing a non-cumulative release of buprenorphine base as        measured in a Franz diffusion cell with dermatomed human skin of        2 μg/cm² to 10 μg/cm² in the first 8 hours,        20 μg/cm² to 80 μg/cm² from hour 8 to hour 24,        20 μg/cm² to 80 μg/cm² from hour 24 to hour 32,        30 μg/cm² to 120 μg/cm² from hour 32 to hour 48,        40 μg/cm² to 150 μg/cm² from hour 48 to hour 72,        100 μg/cm² to 300 μg/cm² from hour 72 to hour 144, and        30 μg/cm² to 100 μg/cm² from hour 144 to hour 168.        188. Transdermal therapeutic system in accordance with item 187,        comprising a buprenorphine base-containing self-adhesive layer        structure comprising    -   A) a buprenorphine base-impermeable backing layer, and    -   B) a buprenorphine base-containing pressure-sensitive adhesive        layer on said buprenorphine base-impermeable backing layer, the        adhesive layer comprising        -   a) at least one polymer-based pressure-sensitive adhesive,            and        -   b) an analgesically effective amount of buprenorphine base,            wherein said buprenorphine base-containing            pressure-sensitive adhesive layer is the skin contact layer.            189. Transdermal therapeutic system comprising buprenorphine            for the transdermal administration of buprenorphine, wherein            buprenorphine is present in the form of buprenorphine base            and providing a non-cumulative release of buprenorphine base            as measured in a Franz diffusion cell with dermatomed human            skin of            2 μg/cm² to 10 μg/cm² in the first 8 hours,            20 μg/cm² to 80 μg/cm² from hour 8 to hour 24,            20 μg/cm² to 80 μg/cm² from hour 24 to hour 32,            30 μg/cm² to 120 μg/cm² from hour 32 to hour 48,            40 μg/cm² to 150 μg/cm² from hour 48 to hour 72,            100 μg/cm² to 300 μg/cm² from hour 72 to hour 144, and            30 μg/cm² to 100 μg/cm² from hour 144 to hour 168, and            comprising a buprenorphine base-containing self-adhesive            layer structure comprising    -   A) a buprenorphine base-impermeable backing layer, and    -   B) a buprenorphine base-containing pressure-sensitive adhesive        layer on said buprenorphine base-impermeable backing layer, the        adhesive layer comprising        -   a) at least one polymer-based pressure-sensitive adhesive,        -   b) an analgesically effective amount of buprenorphine base,            and        -   c) a carboxylic acid selected from the group consisting of            oleic acid, linoleic acid, linolenic acid, levulinic acid            and mixtures thereof, in an amount sufficient so that said            analgesically effective amount of buprenorphine base is            solubilized therein to form a mixture, and the carboxylic            acid buprenorphine base solution forms dispersed deposits in            the said pressure-sensitive adhesive,            wherein said buprenorphine base-containing            pressure-sensitive adhesive layer is the skin contact layer.            190. Transdermal therapeutic system in accordance with any            one of items 1 to 189 for use in a method of treating pain.            191. Transdermal therapeutic system in accordance with any            one of items 1 to 189 for use in a method of treating pain            by applying a transdermal therapeutic system for more than            96 hours on the skin of a patient.            192. Transdermal therapeutic system in accordance with any            one of items 1 to 189 for use in a method of treating pain            by applying a transdermal therapeutic system for more than 4            days on the skin of a patient.            193. Transdermal therapeutic system in accordance with any            one of items 1 to 189 for use in a method of treating pain            by applying a transdermal therapeutic system for about 120            hours on the skin of a patient.            194. Transdermal therapeutic system in accordance with any            one of items 1 to 189 for use in a method of treating pain            by applying a transdermal therapeutic system for 5 days on            the skin of a patient.            195. Transdermal therapeutic system in accordance with any            one of items 1 to 189 for use in a method of treating pain            by applying a transdermal therapeutic system for about 144            hours on the skin of a patient.            196. Transdermal therapeutic system in accordance with any            one of items 1 to 189 for use in a method of treating pain            by applying a transdermal therapeutic system for 6 days on            the skin of a patient.            197. Transdermal therapeutic system in accordance with any            one of items 1 to 189 for use in a method of treating pain            by applying a transdermal therapeutic system for about 168            hours on the skin of a patient.            198. Transdermal therapeutic system in accordance with any            one of items 1 to 189 for use in a method of treating pain            by applying a transdermal therapeutic system for 7 days on            the skin of a patient.            199. Transdermal therapeutic system in accordance with any            one of items 1 to 189 for use in a method of treating pain            by applying a transdermal therapeutic system for a week on            the skin of a patient.            200. Method of treating pain in a patient by applying a            transdermal therapeutic system in accordance with any one of            items 1 to 189 for more than 96 hours on the skin of a            patient.            201. Method of treating pain in a patient by applying a            transdermal therapeutic system in accordance with any one of            items 1 to 189 for more than 4 days on the skin of a            patient.            202. Method of treating pain in a patient by applying a            transdermal therapeutic system in accordance with any one of            items 1 to 189 for about 120 hours on the skin of a patient.            203. Method of treating pain in a patient by applying a            transdermal therapeutic system in accordance with any one of            items 1 to 189 for 5 days on the skin of a patient.            204. Method of treating pain in a patient by applying a            transdermal therapeutic system in accordance with any one of            items 1 to 189 for about 144 hours on the skin of a patient.            205. Method of treating pain in a patient by applying a            transdermal therapeutic system in accordance with any one of            items 1 to 189 for 6 days on the skin of a patient.            206. Method of treating pain in a patient by applying a            transdermal therapeutic system in accordance with any one of            items 1 to 189 for about 168 hours on the skin of a patient.            207. Method of treating pain in a patient by applying a            transdermal therapeutic system in accordance with any one of            items 1 to 189 for 7 days on the skin of a patient.            208. Method of treating pain in a patient by applying a            transdermal therapeutic system in accordance with any one of            items 1 to 189 for a week on the skin of a patient.            209. Use of a transdermal therapeutic system in accordance            with any one of items 1 to 199 for the manufacture of a            medicament for the treatment of pain.            210. Use of a transdermal therapeutic system for the            manufacture of a medicament in a method of treating pain in            accordance with any one of claims 200 to 208.            211. Method of manufacture of a transdermal therapeutic            system for the transdermal administration of buprenorphine            in accordance with any one of items 1 to 199, comprising the            steps of    -   1. providing a buprenorphine-containing adhesive mixture or        solution comprising        -   a) buprenorphine base or a pharmaceutically acceptable salt            thereof        -   b) a carboxylic acid,        -   c) a polymer-based pressure-sensitive adhesive, and        -   d) solvent    -   2. coating said buprenorphine-containing adhesive mixture or        solution on a film in an amount to provide the desired coating        dry weight,    -   3. drying said coated buprenorphine-containing adhesive mixture        or solution to provide a buprenorphine-containing adhesive layer        with the desired coating dry weight,    -   4. laminating said buprenorphine-containing adhesive layer to a        backing layer to provide an buprenorphine-containing        self-adhesive layer structure,    -   5. punching the individual systems from the        buprenorphine-containing self-adhesive layer structure with the        desired area of release, and    -   6. optionally adhering to the individual systems an active-free        self-adhesive layer structure comprising also a backing layer        and an active agent-free pressure-sensitive adhesive layer and        which is larger than the individual systems of        buprenorphine-containing self-adhesive layer structure.        212. Method in accordance with item 211, wherein in step 1        buprenorphine is present in the form of buprenorphine base and        the carboxylic acid is levulinic acid and are suspended in        ethanol and subsequently combined with a polymer-based        pressure-sensitive adhesive based on polysiloxane in heptane to        provide the buprenorphine-containing adhesive mixture or        solution.        213. Method of treating pain in a patient by applying for about        168 hours on the skin of a patient a transdermal therapeutic        system for the transdermal administration of buprenorphine,        comprising a buprenorphine-containing self-adhesive layer        structure comprising    -   A) a buprenorphine-impermeable backing layer, and    -   B) a buprenorphine-containing pressure-sensitive adhesive layer        on said buprenorphine-impermeable backing layer, the adhesive        layer comprising        -   a) at least one polymer-based pressure-sensitive adhesive,        -   b) an analgesically effective amount of buprenorphine base            or a pharmaceutically acceptable salt thereof, and        -   c) a carboxylic acid selected from the group consisting of            oleic acid, linoleic acid and linolenic acid, levulinic acid            and mixtures thereof, in an amount sufficient so that said            analgesically effective amount of buprenorphine is            solubilized therein to form a mixture, and the carboxylic            acid buprenorphine mixture forms dispersed deposits in the            said pressure-sensitive adhesive,            wherein said buprenorphine-containing pressure-sensitive            adhesive layer is the skin contact layer.            214. Transdermal therapeutic system for administration of            buprenorphine, comprising a buprenorphine-containing            self-adhesive layer structure comprising    -   A) a buprenorphine-impermeable backing layer, and    -   B) a buprenorphine-containing pressure-sensitive adhesive layer        on said buprenorphine-impermeable backing layer, the adhesive        layer comprising        -   a) at least one polymer-based pressure-sensitive adhesive,        -   b) an analgesically effective amount of buprenorphine base            or a pharmaceutically acceptable salt thereof, and        -   c) a carboxylic acid selected from the group consisting of            oleic acid, linoleic acid, linolenic acid, levulinic acid            and mixtures thereof, in an amount sufficient so that said            analgesically effective amount of buprenorphine is            solubilized therein to form a mixture, and the carboxylic            acid buprenorphine mixture forms dispersed deposits in the            said pressure-sensitive adhesive,            wherein said buprenorphine-containing pressure-sensitive            adhesive layer is the skin contact layer for use in a method            of treating pain by applying said transdermal therapeutic            system for about 168 hours on the skin of a patient.            215. Transdermal therapeutic system for the transdermal            administration of buprenorphine base, comprising a            buprenorphine base-containing self-adhesive layer structure            comprising    -   A) a buprenorphine base-impermeable backing layer, and    -   B) a buprenorphine base-containing pressure-sensitive adhesive        layer on said buprenorphine base-impermeable backing layer, the        adhesive layer comprising        -   a) at least one pressure-sensitive adhesive based on            polysiloxane,        -   b) an analgesically effective amount of buprenorphine base,            and        -   c) levulinic acid, in an amount sufficient so that said            analgesically effective amount of buprenorphine base is            solubilized therein to form a mixture, and the levulinic            acid buprenorphine base mixture forms dispersed deposits in            the said pressure-sensitive adhesive,            wherein said buprenorphine base-containing            pressure-sensitive adhesive layer is the skin contact layer.            216. Method of treating pain in a patient by applying to the            skin of said patient for about 168 hours a transdermal            therapeutic system, comprising a buprenorphine            base-containing self-adhesive layer structure comprising    -   A) a buprenorphine base-impermeable backing layer, and    -   B) a buprenorphine base-containing pressure-sensitive adhesive        layer on said buprenorphine base-impermeable backing layer, the        adhesive layer comprising        -   a) at least one pressure-sensitive adhesive based on            polysiloxane,        -   b) an analgesically effective amount of buprenorphine base,            and        -   c) levulinic acid, in an amount sufficient so that said            analgesically effective amount of buprenorphine base is            solubilized therein to form a mixture, and the levulinic            acid buprenorphine base mixture forms dispersed deposits in            the said pressure-sensitive adhesive,            wherein said buprenorphine base-containing            pressure-sensitive adhesive layer is the skin contact layer.            217. Transdermal therapeutic system for the transdermal            administration of buprenorphine base, comprising a            buprenorphine base-containing self-adhesive layer structure            comprising    -   A) a buprenorphine base-impermeable backing layer, and    -   B) a buprenorphine base-containing pressure-sensitive adhesive        layer on said buprenorphine base-impermeable backing layer, the        adhesive layer comprising        -   a) at least one pressure-sensitive adhesive based on            polysiloxane,        -   b) an analgesically effective amount of buprenorphine base,            and        -   c) levulinic acid, in an amount sufficient so that said            analgesically effective amount of buprenorphine base is            solubilized therein to form a mixture, and the levulinic            acid buprenorphine base mixture forms dispersed deposits in            the said pressure-sensitive adhesive,            wherein said buprenorphine base-containing            pressure-sensitive adhesive layer is the skin contact layer            for use in a method of treating pain by applying said            transdermal therapeutic system for about 168 hours on the            skin of a patient.            218. Transdermal therapeutic system for the transdermal            administration of buprenorphine, comprising a            buprenorphine-containing self-adhesive layer structure            comprising    -   A) a buprenorphine-impermeable backing layer, and    -   B) a buprenorphine-containing pressure-sensitive adhesive layer        on said buprenorphine-impermeable backing layer, the adhesive        layer comprising        -   a) at least one polymer-based pressure-sensitive adhesive,        -   b) an analgesically effective amount of buprenorphine base            or a pharmaceutically acceptable salt thereof, and        -   c) a carboxylic acid selected from the group consisting of            oleic acid, linoleic acid, linolenic acid, levulinic acid            and mixtures thereof, in an amount sufficient so that said            analgesically effective amount of buprenorphine is            solubilized therein to form a mixture, and the carboxylic            acid buprenorphine solution forms dispersed deposits in the            said pressure-sensitive adhesive,            wherein said buprenorphine-containing pressure-sensitive            adhesive layer is the skin contact layer and contains more            than about 0.55 mg/cm² or more than 0.6 mg/cm² of            buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            219. Method of treating pain in a patient by applying to the            skin of said patient for            about 168 hours a transdermal therapeutic system for the            transdermal administration of buprenorphine, comprising a            buprenorphine-containing self-adhesive layer structure            comprising    -   A) a buprenorphine-impermeable backing layer, and    -   B) a buprenorphine-containing pressure-sensitive adhesive layer        on said buprenorphine-impermeable backing layer, the adhesive        layer comprising        -   a) at least one polymer-based pressure-sensitive adhesive,        -   b) an analgesically effective amount of buprenorphine base            or a pharmaceutically acceptable salt thereof, and        -   c) a carboxylic acid selected from the group consisting of            oleic acid, linoleic acid, linolenic acid, levulinic acid            and mixtures thereof, in an amount sufficient so that said            analgesically effective amount of buprenorphine is            solubilized therein to form a mixture, and the carboxylic            acid buprenorphine solution forms dispersed deposits in the            said pressure-sensitive adhesive,            wherein said buprenorphine-containing pressure-sensitive            adhesive layer is the skin contact layer and contains more            than about 0.55 mg/cm² or more than 0.6 mg/cm² of            buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof.            220. Transdermal therapeutic system for the transdermal            administration of buprenorphine, comprising a            buprenorphine-containing self-adhesive layer structure            comprising    -   A) a buprenorphine-impermeable backing layer, and    -   B) a buprenorphine-containing pressure-sensitive adhesive layer        on said buprenorphine-impermeable backing layer, the adhesive        layer comprising        -   a) at least one polymer-based pressure-sensitive adhesive,        -   b) an analgesically effective amount of buprenorphine base            or a pharmaceutically acceptable salt thereof, and        -   c) a carboxylic acid selected from the group consisting of            oleic acid, linoleic acid, linolenic acid, levulinic acid            and mixtures thereof, in an amount sufficient so that said            analgesically effective amount of buprenorphine is            solubilized therein to form a mixture, and the carboxylic            acid buprenorphine solution forms dispersed deposits in the            said pressure-sensitive adhesive,            wherein said buprenorphine-containing pressure-sensitive            adhesive layer is the skin contact layer and contains more            than about 0.55 mg/cm² or more than 0.6 mg/cm² of            buprenorphine base or an equimolar amount of a            pharmaceutically acceptable salt thereof for use in a method            of treating pain by applying said transdermal therapeutic            system for about 168 hours on the skin of a patient.            221. Transdermal therapeutic system for the transdermal            administration of buprenorphine base, comprising a            buprenorphine base-containing self-adhesive layer structure            comprising    -   A) a buprenorphine base-impermeable backing layer, and    -   B) a buprenorphine base-containing pressure-sensitive adhesive        layer on said buprenorphine base-impermeable backing layer, the        adhesive layer comprising        -   a) at least one pressure-sensitive adhesive based on            polysiloxanes,        -   b) an analgesically effective amount of buprenorphine base,            and        -   c) levulinic acid, in an amount sufficient so that said            analgesically effective amount of buprenorphine base is            solubilized therein to form a mixture, and the levulinic            acid buprenorphine base mixture forms dispersed deposits in            the said pressure-sensitive adhesive,            wherein said buprenorphine base-containing            pressure-sensitive adhesive layer is the skin contact layer            and contains more than about 0.55 mg/cm² or more than 0.6            mg/cm² of buprenorphine base.            222. Method of treating pain in a patient by applying to the            skin of said patient for about 168 hours a transdermal            therapeutic system for the transdermal administration of            buprenorphine base, comprising a buprenorphine            base-containing self-adhesive layer structure comprising    -   A) a buprenorphine base-impermeable backing layer, and    -   B) a buprenorphine base-containing pressure-sensitive adhesive        layer on said buprenorphine base-impermeable backing layer, the        adhesive layer comprising        -   a) at least one pressure-sensitive adhesive based on            polysiloxanes,        -   b) an analgesically effective amount of buprenorphine base,            and        -   c) levulinic acid, in an amount sufficient so that said            analgesically effective amount of buprenorphine base is            solubilized therein to form a mixture, and the levulinic            acid buprenorphine base mixture forms dispersed deposits in            the said pressure-sensitive adhesive,            wherein said buprenorphine base-containing            pressure-sensitive adhesive layer is the skin contact layer            and contains more than about 0.55 mg/cm² or more than 0.6            mg/cm² of buprenorphine base.            223. Transdermal therapeutic system for the transdermal            administration of buprenorphine base, comprising a            buprenorphine base-containing self-adhesive layer structure            comprising    -   A) a buprenorphine base-impermeable backing layer, and    -   B) a buprenorphine base-containing pressure-sensitive adhesive        layer on said buprenorphine base-impermeable backing layer, the        adhesive layer comprising        -   a) at least one pressure-sensitive adhesive based on            polysiloxanes,        -   b) an analgesically effective amount of buprenorphine base,            and        -   c) levulinic acid, in an amount sufficient so that said            analgesically effective amount of buprenorphine base is            solubilized therein to form a mixture, and the levulinic            acid buprenorphine base mixture forms dispersed deposits in            the said pressure-sensitive adhesive,            wherein said buprenorphine base-containing            pressure-sensitive adhesive layer is the skin contact layer            and contains more than about 0.55 mg/cm² or more than 0.6            mg/cm² of buprenorphine base for use in a method of treating            pain by applying said transdermal therapeutic system for            about 168 hours on the skin of a patient.            224. A set of two to five different transdermal therapeutic            systems for the transdermal administration of buprenorphine            base selected from five different transdermal therapeutic            systems, a first, a second, a third, a forth and a fifth            transdermal therapeutic system, each of the five different            transdermal therapeutic systems comprising a            buprenorphine-containing self-adhesive layer structure            comprising    -   A) a buprenorphine base-impermeable backing layer, and    -   B) a buprenorphine base-containing pressure-sensitive adhesive        layer on said buprenorphine base-impermeable backing layer, the        adhesive layer comprising        -   a) at least one pressure-sensitive adhesive based on            polysiloxanes,        -   b) an analgesically effective amount of buprenorphine base,            and        -   c) levulinic acid, in an amount sufficient so that said            analgesically effective amount of buprenorphine base is            solubilized therein to form a mixture, and the levulinic            acid buprenorphine base mixture forms dispersed deposits in            the said pressure-sensitive adhesive,            wherein,            the first transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 1 cm²            to about 4.8 cm² and contains from about 1 mg to about 4 mg            buprenorphine base;            the second transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 3 cm²            to about 9.5 cm² and contains from about 3.5 mg to about 8            mg buprenorphine base; and            the third transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 6 cm²            to about 19 cm² and contains from about 6.5 mg to about 16            mg buprenorphine base; and            the fourth transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 12            cm² to about 28.5 cm² and contains from about 11.5 mg to            about 24 mg buprenorphine base; and            the fifth transdermal therapeutic system provides a size of            said buprenorphine-containing pressure-sensitive adhesive            layer providing the area of release ranging from about 16            cm² to about 38 cm² from about 15 mg to about 32 mg            buprenorphine base,            wherein the five different transdermal therapeutic systems            have increasing areas of release and amounts of            buprenorphine from the first to the fifth transdermal            therapeutic system for use in method of treating pain by            applying one of said transdermal therapeutic systems for            about 168 hours on the skin of a patient.

1. Transdermal therapeutic system for the transdermal administration ofbuprenorphine, comprising a buprenorphine-containing self-adhesive layerstructure comprising A) a buprenorphine-impermeable backing layer, andB) a buprenorphine-containing pressure-sensitive adhesive layer on saidbuprenorphine-impermeable backing layer, the adhesive layer comprisinga) at least one polymer-based pressure-sensitive adhesive, b) ananalgesically effective amount of buprenorphine base or apharmaceutically acceptable salt thereof, and c) a carboxylic acidselected from the group consisting of oleic acid, linoleic acid,linolenic acid, levulinic acid and mixtures thereof; in an amountsufficient so that said analgesically effective amount of buprenorphineis solubilized therein to form a mixture, and the carboxylic acidbuprenorphine mixture forms dispersed deposits in the saidpressure-sensitive adhesive, wherein said buprenorphine-containingpressure-sensitive adhesive layer is the skin contact layer. 2.Transdermal therapeutic system in accordance with claim 1, wherein saidbuprenorphine is present in the form of buprenorphine base. 3.Transdermal therapeutic system in accordance with claim 1, wherein saidcarboxylic acid is levulinic acid.
 4. Transdermal therapeutic system inaccordance with claim 1, wherein said buprenorphine is present in theform of buprenorphine base and said carboxylic acid is levulinic acid.5. Transdermal therapeutic system in accordance with claim 1, whereinsaid polymer-based pressure-sensitive adhesive is based on polysiloxanesor polyisobutylenes.
 6. Transdermal therapeutic system in accordancewith claim 1, wherein said polymer-based pressure-sensitive adhesive isbased on polysiloxanes.
 7. Transdermal therapeutic system in accordancewith claim 1, wherein said buprenorphine is present in the form ofbuprenorphine base, said carboxylic acid is levulinic acid and thepolymer-based pressure-sensitive adhesive is based on polysiloxanes. 8.Transdermal therapeutic system in accordance with any one of claims 1 to7, the amount of said buprenorphine contained in the transdermaltherapeutic system ranging from about 1 mg to about 4 mg buprenorphinebase or an equimolar amount of a pharmaceutically acceptable saltthereof, or about 3.5 mg to about 8 mg buprenorphine base or anequimolar amount of a pharmaceutically acceptable salt thereof, or about6.5 mg to about 16 mg buprenorphine base or an equimolar amount of apharmaceutically acceptable salt thereof, or about 11.5 mg to about 24mg buprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof, or about 15 mg to about 32 mg buprenorphinebase or an equimolar amount of a pharmaceutically acceptable saltthereof.
 9. Transdermal therapeutic system in accordance with any one ofclaims 1 to 8, the size of said buprenorphine-containingpressure-sensitive adhesive layer providing the area of release rangingfrom about 1 cm² to about 4.8 cm², or about 3 cm² to about 9.5 cm², orabout 6 cm² to about 19 cm², or about 12 cm² to about 28.5 cm², or about16 cm² to about 38 cm².
 10. Transdermal therapeutic system in accordancewith any one of claims 1 to 7, the size of said buprenorphine-containingpressure-sensitive adhesive layer providing the area of release rangingfrom about 1 cm² to about 4.8 cm² and the amount of said buprenorphinecontained in the transdermal therapeutic system ranging from about 1 mgto about 4 mg buprenorphine base or an equimolar amount of apharmaceutically acceptable salt thereof.
 11. Transdermal therapeuticsystem in accordance with claim 10, said transdermal therapeutic systemproviding a mean AUCt of more than 7,000 pg·hr/ml over about 168 hoursof administration after a single-dose administration to a subjectpopulation.
 12. Transdermal therapeutic system in accordance with claim11, said transdermal therapeutic system providing a mean AUCt of morethan 8,000 pg·hr/ml over about 168 hours of administration after asingle-dose administration to a subject population.
 13. Transdermaltherapeutic system in accordance with any one of claims 10 to 12,wherein the transdermal therapeutic system provides a nominal meanrelease rate of about 5 μg/hr over about 168 hours of administration.14. Transdermal therapeutic system in accordance with any one of claims10 to 13, wherein buprenorphine is present in the form of buprenorphinebase and wherein the transdermal therapeutic system when tested in acomparative clinical study is bioequivalent to the commercial productBuTrans® having an area of release of 6.25 cm².
 15. Transdermaltherapeutic system in accordance with any one of claims 1 to 7, the sizeof said buprenorphine-containing pressure-sensitive adhesive layerproviding the area of release ranging from about 3 cm² to about 9.5 cm²,and the amount of said buprenorphine contained in the transdermaltherapeutic system ranging from about 3.5 mg to about 8 mg buprenorphinebase or an equimolar amount of a pharmaceutically acceptable saltthereof.
 16. Transdermal therapeutic system in accordance with claim 15,said transdermal therapeutic system providing a mean AUCt of more than14,000 pg·hr/ml over about 168 hours of administration after asingle-dose administration to a subject population.
 17. Transdermaltherapeutic system in accordance with claim 16, said transdermaltherapeutic system providing a mean AUCt of more than 16,000 pg·hr/mlover about 168 hours of administration after a single-doseadministration to a subject population.
 18. Transdermal therapeuticsystem in accordance with any one of claims 15 to 17, wherein thetransdermal therapeutic system provides a nominal mean release rate ofabout 10 μg/hr over about 168 hours of administration.
 19. Transdermaltherapeutic system in accordance with any one of claims 15 to 18,wherein buprenorphine is present in the form of buprenorphine base andwherein the transdermal therapeutic system when tested in a comparativeclinical study is bioequivalent to the commercial product BuTrans®having an area of release of 12.5 cm².
 20. Transdermal therapeuticsystem in accordance with any one of claims 1 to 7, the size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 6 cm² to about 19 cm² and the amountof said buprenorphine contained in the transdermal therapeutic systemranging from about 6.5 mg to about 16 mg buprenorphine base or anequimolar amount of a pharmaceutically acceptable salt thereof. 21.Transdermal therapeutic system in accordance with claim 20, saidtransdermal therapeutic system providing a mean AUCt of more than 28,000pg·hr/ml over about 168 hours of administration after a single-doseadministration to a subject population.
 22. Transdermal therapeuticsystem in accordance with claim 21, said transdermal therapeutic systemproviding a mean AUCt of more than 32,000 pg·hr/ml over about 168 hoursof administration after a single-dose administration to a subjectpopulation.
 23. Transdermal therapeutic system in accordance with anyone of claims 20 to 22, wherein the transdermal therapeutic systemprovides a nominal mean release rate of about 20 μg/hr over about 168hours of administration.
 24. Transdermal therapeutic system inaccordance with any one of claims 20 to 23, wherein buprenorphine ispresent in the form of buprenorphine base and wherein the transdermaltherapeutic system when tested in a comparative clinical study isbioequivalent to the commercial product BuTrans® having an area ofrelease of 25 cm².
 25. Transdermal therapeutic system in accordance withany one of claims 1 to 7, the size of said buprenorphine-containingpressure-sensitive adhesive layer providing the area of release rangingfrom about 12 cm² to about 28.5 cm², and the amount of saidbuprenorphine contained in the transdermal therapeutic system rangingfrom about 11.5 mg to about 24 mg buprenorphine base or an equimolaramount of a pharmaceutically acceptable salt thereof.
 26. Transdermaltherapeutic system in accordance with claim 25, said transdermaltherapeutic system providing a mean AUCt of more than 42,000 pg·hr/mlover about 168 hours of administration after a single-doseadministration to a subject population.
 27. Transdermal therapeuticsystem in accordance with claim 26, said transdermal therapeutic systemproviding a mean AUCt of more than 48,000 pg·hr/ml over about 168 hoursof administration after a single-dose administration to a subjectpopulation.
 28. Transdermal therapeutic system in accordance with anyone of claims 25 to 27, wherein the transdermal therapeutic systemprovides a nominal mean release rate of about 30 μg/hr over about 168hours of administration.
 29. Transdermal therapeutic system inaccordance with any one of claims 1 to 7, the size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 16 cm² to about 38 cm², and theamount of said buprenorphine contained in the transdermal therapeuticsystem ranging from about 15 mg to about 32 mg buprenorphine base or anequimolar amount of a pharmaceutically acceptable salt thereof. 30.Transdermal therapeutic system in accordance with claim 29, saidtransdermal therapeutic system providing a mean AUCt of more than 62,000pg·hr/ml over about 168 hours of administration after a single-doseadministration to a subject population.
 31. Transdermal therapeuticsystem in accordance with claim 30, said transdermal therapeutic systemproviding a mean AUCt of more than 64,000 pg·hr/ml over about 168 hoursof administration after a single-dose administration to a subjectpopulation.
 32. Transdermal therapeutic system in accordance with anyone of claims 29 to 31, wherein the transdermal therapeutic systemprovides a nominal mean release rate of about 40 μg/hr over about 168hours of administration.
 33. Transdermal therapeutic system inaccordance with any one of claims 1 to 32, said transdermal therapeuticsystem providing an arithmetic mean tmax of from about 60 hr to about120 hr after a single-dose administration to a subject population. 34.Transdermal therapeutic system in accordance with claim 33, saidtransdermal therapeutic system providing an arithmetic mean tmax of fromabout 66 hr to less than 108 hr after a single-dose administration to asubject population.
 35. Transdermal therapeutic system in accordancewith any one of claims 1 to 34, said transdermal therapeutic systemproviding a mean AUCt per area of release of more than 1,700pg·hr/ml-cm² over about 168 hours of administration after a single-doseadministration to a subject population.
 36. Transdermal therapeuticsystem in accordance with any one of claims 1 to 35, saidbuprenorphine-containing pressure-sensitive adhesive layer containingmore than 0.55 mg/cm² of buprenorphine base or an equimolar amount of apharmaceutically acceptable salt thereof.
 37. Transdermal therapeuticsystem in accordance with claim 36, said buprenorphine-containingpressure-sensitive adhesive layer containing more than 0.6 mg/cm² ofbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof.
 38. Transdermal therapeutic system inaccordance with any one of claims 1 to 37, the buprenorphine-containingpressure-sensitive adhesive layer being coated at a dry weight of morethan 6 mg/cm².
 39. Transdermal therapeutic system in accordance withclaim 38, the buprenorphine-containing pressure-sensitive adhesive layerbeing coated at a dry weight of more than 8 mg/cm².
 40. Transdermaltherapeutic system in accordance with any one of claims 1 to 39, whereinthe carboxylic acid is levulinic acid, said buprenorphine-containingpressure-sensitive adhesive layer containing the same % amounts oflevulinic acid and buprenorphine, based on the % amount of buprenorphinebase.
 41. Transdermal therapeutic system in accordance with any one ofclaims 1 to 39, wherein the carboxylic acid is levulinic acid, saidbuprenorphine-containing pressure-sensitive adhesive layer containingless % amounts of levulinic acid than % amounts of buprenorphine, basedon the % amount of buprenorphine base.
 42. Transdermal therapeuticsystem in accordance with any one of claims 1 to 41, saidbuprenorphine-containing self-adhesive layer structure being attached toa second larger active agent-free self-adhesive layer structure forenhancing the adhesive properties of the overall transdermal therapeuticsystem.
 43. Transdermal therapeutic system in accordance with claim 42,said second active-free self-adhesive layer structure comprising abacking layer and an active agent-free pressure-sensitive adhesive layerof pressure-sensitive adhesive based on polyacrylates.
 44. Transdermaltherapeutic system in accordance with claim 42, said second active-freeself-adhesive layer structure comprising a backing layer and an activeagent-free pressure-sensitive adhesive layer of pressure-sensitiveadhesive based on polysiloxane.
 45. Transdermal therapeutic system inaccordance with any one of claims 1 to 44, wherein buprenorphine ispresent in the form of buprenorphine base and providing a meancumulative skin permeation rate measured in a Franz diffusion cell withdermatomed human skin of more than 1.3 μg/cm²-hr over a 168 hours test.46. Transdermal therapeutic system in accordance with any one of claims1 to 45, wherein buprenorphine is present in the form of buprenorphinebase and providing a cumulative release of buprenorphine base asmeasured in a Franz diffusion cell with dermatomed human skin of 220μg/cm² to 640 μg/cm² over a time period of 168 hours.
 47. Transdermaltherapeutic system in accordance with any one of claims 1 to 46, whereinbuprenorphine is present in the form of buprenorphine base and providinga non-cumulative release of buprenorphine base as measured in a Franzdiffusion cell with dermatomed human skin of 2 μg/cm² to 10 μg/cm² inthe first 8 hours, 20 μg/cm² to 80 μg/cm² from hour 8 to hour 24, 20μg/cm² to 80 μg/cm² from hour 24 to hour 32, 30 μg/cm² to 120 μg/cm²from hour 32 to hour 48, 40 μg/cm² to 150 μg/cm² from hour 48 to hour72, 100 μg/cm² to 300 μg/cm² from hour 72 to hour 144, and 30 μg/cm² to100 μg/cm² from hour 144 to hour
 168. 48. A set of two to five differenttransdermal therapeutic systems each in accordance with any one ofclaims 1 to 47, wherein the first transdermal therapeutic systemprovides a size of said buprenorphine-containing pressure-sensitiveadhesive layer providing the area of release ranging from about 1 cm² toabout 4.8 cm² and contains an amount of said buprenorphine from about 1mg to about 4 mg buprenorphine base or an equimolar amount of apharmaceutically acceptable salt thereof; the second transdermaltherapeutic system provides a size of said buprenorphine-containingpressure-sensitive adhesive layer providing the area of release rangingfrom about 3 cm² to about 9.5 cm² and contains an amount of saidbuprenorphine from about 3.5 mg to about 8 mg buprenorphine base or anequimolar amount of a pharmaceutically acceptable salt thereof; and thethird transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 6 cm² to about 19 cm² and contains anamount of said buprenorphine from about 6.5 mg to about 16 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof; and the fourth transdermal therapeutic systemprovides a size of said buprenorphine-containing pressure-sensitiveadhesive layer providing the area of release ranging from about 12 cm²to about 28.5 cm² and contains an amount of said buprenorphine fromabout 11.5 mg to about 24 mg buprenorphine base or an equimolar amountof a pharmaceutically acceptable salt thereof; and the fifth transdermaltherapeutic system provides a size of said buprenorphine-containingpressure-sensitive adhesive layer providing the area of release rangingfrom about 16 cm² to about 38 cm² and contains an amount of saidbuprenorphine from about 15 mg to about 32 mg buprenorphine base or anequimolar amount of a pharmaceutically acceptable salt thereof. 49.Transdermal therapeutic system selected from a set in accordance withclaim 48, wherein buprenorphine is present in the form of buprenorphinebase and wherein the first transdermal therapeutic system when tested ina comparative clinical study is bioequivalent to a reference producthaving an area of release of about 6.25 cm² and providing a nominal meanrelease rate of about 5 μg/hr over about 168 hours of administration,the second transdermal therapeutic system when tested in a comparativeclinical study is bioequivalent to a reference product having an area ofrelease of about 12.5 cm² and providing a nominal mean release rate ofabout 10 μg/hr over about 168 hours of administration, the thirdtransdermal therapeutic system when tested in a comparative clinicalstudy is bioequivalent to a reference product having an area of releaseof about 25 cm² and providing a nominal mean release rate of about 20μg/hr over about 168 hours of administration, the fourth transdermaltherapeutic system when tested in a comparative clinical study isbioequivalent to a reference product having an area of release of about37.5 cm² and providing a nominal mean release rate of about 30 μg/hrover about 168 hours of administration, the fifth transdermaltherapeutic system when tested in a comparative clinical study isbioequivalent to a reference product having an area of release of about50 cm² and providing a nominal mean release rate of about 40 μg/hr overabout 168 hours of administration, wherein the reference product isprepared by the following steps:
 1. homogenizing of 1,139 g of a 47.83%polyacrylate solution of a self-crosslinked acrylate copolymer of2-ethylhexyl acrylate, vinyl acetate, acrylic acid (solvent: ethylacetate:heptanes:isopropanol:toluene:acetylacetonate in the ratio of37:26:26:4:1), 100 g of levulinic acid, 150 g of oleyl oleate, 100 g ofpolyvinylpyrrolidone, 150 g of ethanol, 200 g of ethyl acetate, and 100g of buprenorphine base to provide a mixture;
 2. stirring the mixture ofstep 1 for about 2 hours and controlling the dissolution of all solidsvisually whereas controlling the evaporation loss by reweighing andreplenishing the possible solvent loss by ethyl acetate;
 3. subsequentlyapplying the mixture on a transparent polyester film in such a mannerthat the mass per unit area of the dry adhesive layer amounts to about80 g/m² wherein the polyester film is rendered removable by means ofsiliconization and serves as protective layer,
 4. removing the solventsof the mixture applied on a transparent polyester film in step 3 bydrying with heated air which is led over a moist lane resulting inevaporation of the solvents, but also in melting of the levulinic acidand covering the adhesive film with a polyester foil;
 5. punching thearea of release of 6.25 cm², 12.5 cm², 25 cm², 37.5 cm² and 50 cm²,respectively, by means of suitable cutting tools and removing the edgesleft between the individual systems.
 50. Transdermal therapeutic systemcomprising buprenorphine for the transdermal administration ofbuprenorphine selected from: a first transdermal therapeutic systemproviding a size of the area of release ranging from about 1 cm² toabout 4.8 cm² and containing an amount of said buprenorphine from 1 mgto about 4 mg buprenorphine base or an equimolar amount of apharmaceutically acceptable salt thereof and providing a mean AUCt ofmore than 8,000 pg·hr/ml over about 168 hours of administration after asingle-dose administration to a subject population; a second transdermaltherapeutic system providing a size of the area of release ranging fromabout 3 cm² to about 9.5 cm² and containing an amount of saidbuprenorphine from about 3.5 mg to about 8 mg buprenorphine base or anequimolar amount of a pharmaceutically acceptable salt thereof andproviding a mean AUCt of more than 16,000 pg·hr/ml over about 168 hoursof administration after a single-dose administration to a subjectpopulation; and a third transdermal therapeutic system providing a sizeof the area of release ranging from about 6 cm² to about 19 cm² andcontaining an amount of said buprenorphine from about 6.5 mg to about 16mg buprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a mean AUCt of more than 32,000pg·hr/ml over about 168 hours of administration after a single-doseadministration to a subject population; and a fourth transdermaltherapeutic system providing a size of the area of release ranging fromabout 12 cm² to about 28.5 cm² and containing an amount of saidbuprenorphine from about 11.5 mg to about 24 mg buprenorphine base or anequimolar amount of a pharmaceutically acceptable salt thereof andproviding a mean AUCt of more than 48,000 pg·hr/ml over about 168 hoursof administration after a single-dose administration to a subjectpopulation; and a fifth transdermal therapeutic system providing a sizeof the area of release ranging from about 16 cm² to about 38 cm² andcontaining an amount of said buprenorphine from about 15 mg to about 32mg buprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a mean AUCt of more than 64,000pg·hr/ml over about 168 hours of administration after a single-doseadministration to a subject population.
 51. Transdermal therapeuticsystem comprising buprenorphine for the transdermal administration ofbuprenorphine selected from: a first transdermal therapeutic systemproviding a size of the area of release ranging from about 1 cm² toabout 4.8 cm² and containing an amount of said buprenorphine from 1 mgto about 4 mg buprenorphine base or an equimolar amount of apharmaceutically acceptable salt thereof and providing a nominal meanrelease rate of about 5 μg/hr over about 168 hours of administration; asecond transdermal therapeutic system providing a size of the area ofrelease ranging from about 3 cm² to about 9.5 cm² and containing anamount of said buprenorphine from about 3.5 mg to about 8 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a nominal mean release rate ofabout 10 μg/hr over about 168 hours of administration; and a thirdtransdermal therapeutic system providing a size of the area of releaseranging from about 6 cm² to about 19 cm² and containing an amount ofsaid buprenorphine from about 6.5 mg to about 16 mg buprenorphine baseor an equimolar amount of a pharmaceutically acceptable salt thereof andproviding a nominal mean release rate of about 20 μg/hr over about 168hours of administration; and a fourth transdermal therapeutic systemproviding a size of the area of release ranging from about 12 cm² toabout 28.5 cm² and containing an amount of said buprenorphine from about11.5 mg to about 24 mg buprenorphine base or an equimolar amount of apharmaceutically acceptable salt thereof and providing a nominal meanrelease rate of about 30 μg/hr over about 168 hours of administration;and a fifth transdermal therapeutic system providing a size of the areaof release ranging from about 16 cm² to about 38 cm² and containing anamount of said buprenorphine from about 15 mg to about 32 mgbuprenorphine base or an equimolar amount of a pharmaceuticallyacceptable salt thereof and providing a nominal mean release rate ofabout 40 μg/hr over about 168 hours of administration.
 52. Transdermaltherapeutic system in accordance with claim 50 or 51, whereinbuprenorphine is present in the form of buprenorphine base and providinga non-cumulative release of buprenorphine base as measured in a Franzdiffusion cell with dermatomed human skin of 2 μg/cm² to 10 μg/cm² inthe first 8 hours, 20 μg/cm² to 80 μg/cm² from hour 8 to hour 24, 20μg/cm² to 80 μg/cm² from hour 24 to hour 32, 30 μg/cm² to 120 μg/cm²from hour 32 to hour 48, 40 μg/cm² to 150 μg/cm² from hour 48 to hour72, 100 μg/cm² to 300 μg/cm² from hour 72 to hour 144, and 30 μg/cm² to100 μg/cm² from hour 144 to hour
 168. 53. A set of transdermaltherapeutic systems including at least two transdermal therapeuticsystems selected from the first, second, third, fourth and fifthtransdermal therapeutic system in accordance with any one of claims 50to
 52. 54. Transdermal therapeutic system comprising buprenorphine forthe transdermal administration of buprenorphine, wherein buprenorphineis present in the form of buprenorphine base and providing anon-cumulative release of buprenorphine base as measured in a Franzdiffusion cell with dermatomed human skin of 2 μg/cm² to 10 μg/cm² inthe first 8 hours, 20 μg/cm² to 80 μg/cm² from hour 8 to hour 24, 20μg/cm² to 80 μg/cm² from hour 24 to hour 32, 30 μg/cm² to 120 μg/cm²from hour 32 to hour 48, 40 μg/cm² to 150 μg/cm² from hour 48 to hour72, 100 μg/cm² to 300 μg/cm² from hour 72 to hour 144, and 30 μg/cm² to100 μg/cm² from hour 144 to hour
 168. 55. Transdermal therapeutic systemin accordance with claim 54, comprising a buprenorphine base-containingself-adhesive layer structure comprising A) a buprenorphinebase-impermeable backing layer, and B) a buprenorphine base-containingpressure-sensitive adhesive layer on said buprenorphine base-impermeablebacking layer, the adhesive layer comprising a) at least onepolymer-based pressure-sensitive adhesive, and b) an analgesicallyeffective amount of buprenorphine base, wherein said buprenorphinebase-containing pressure-sensitive adhesive layer is the skin contactlayer.
 56. Transdermal therapeutic system comprising buprenorphine forthe transdermal administration of buprenorphine, wherein buprenorphineis present in the form of buprenorphine base and providing anon-cumulative release of buprenorphine base as measured in a Franzdiffusion cell with dermatomed human skin of 2 μg/cm² to 10 μg/cm² inthe first 8 hours, 20 μg/cm² to 80 μg/cm² from hour 8 to hour 24, 20μg/cm² to 80 μg/cm² from hour 24 to hour 32, 30 μg/cm² to 120 μg/cm²from hour 32 to hour 48, 40 μg/cm² to 150 μg/cm² from hour 48 to hour72, 100 μg/cm² to 300 μg/cm² from hour 72 to hour 144, and 30 μg/cm² to100 μg/cm² from hour 144 to hour 168, and comprising a buprenorphinebase-containing self-adhesive layer structure comprising A) abuprenorphine base-impermeable backing layer, and B) a buprenorphinebase-containing pressure-sensitive adhesive layer on said buprenorphinebase-impermeable backing layer, the adhesive layer comprising a) atleast one polymer-based pressure-sensitive adhesive, b) an analgesicallyeffective amount of buprenorphine base, and c) a carboxylic acidselected from the group consisting of oleic acid, linoleic acid,linolenic acid, levulinic acid and mixtures thereof, in an amountsufficient so that said analgesically effective amount of buprenorphinebase is solubilized therein to form a mixture, and the carboxylic acidbuprenorphine base solution forms dispersed deposits in the saidpressure-sensitive adhesive, wherein said buprenorphine base-containingpressure-sensitive adhesive layer is the skin contact layer. 57.Transdermal therapeutic system in accordance with any one of claims 1 to56 for use in a method of treating pain.
 58. Transdermal therapeuticsystem in accordance with any one of claims 1 to 56 for use in a methodof treating pain by applying a transdermal therapeutic system for morethan 96 hours on the skin of a patient.
 59. Transdermal therapeuticsystem in accordance with any one of claims 1 to 56 for use in a methodof treating pain by applying a transdermal therapeutic system for about120 hours on the skin of a patient.
 60. Transdermal therapeutic systemin accordance with any one of claims 1 to 56 for use in a method oftreating pain by applying a transdermal therapeutic system for about 144hours on the skin of a patient.
 61. Transdermal therapeutic system inaccordance with any one of claims 1 to 56 for use in a method oftreating pain by applying a transdermal therapeutic system for about 168hours on the skin of a patient.
 62. Method of treating pain in a patientby applying a transdermal therapeutic system in accordance with any oneof claims 1 to 56 for more than 96 hours on the skin of a patient. 63.Method of treating pain in a patient by applying a transdermaltherapeutic system in accordance with any one of claims 1 to 56 forabout 120 hours on the skin of a patient.
 64. Method of treating pain ina patient by applying a transdermal therapeutic system in accordancewith any one of claims 1 to 56 for about 144 hours on the skin of apatient.
 65. Method of treating pain in a patient by applying atransdermal therapeutic system in accordance with any one of claims 1 to56 for about 168 hours on the skin of a patient.
 66. Method ofmanufacture of a transdermal therapeutic system for the transdermaladministration of buprenorphine in accordance with any one of claims 1to 61, comprising the steps of
 1. providing a buprenorphine-containingadhesive mixture or solution comprising a) buprenorphine base or apharmaceutically acceptable salt thereof b) a carboxylic acid, c) apolymer-based pressure-sensitive adhesive, and d) solvent
 2. coatingsaid buprenorphine-containing adhesive mixture or solution on a film inan amount to provide the desired coating dry weight,
 3. drying saidcoated buprenorphine-containing adhesive mixture or solution to providea buprenorphine-containing adhesive layer with the desired coating dryweight,
 4. laminating said buprenorphine-containing adhesive layer to abacking layer to provide an buprenorphine-containing self-adhesive layerstructure,
 5. punching the individual systems from thebuprenorphine-containing self-adhesive layer structure with the desiredarea of release, and
 6. optionally adhering to the individual systems anactive-free self-adhesive layer structure comprising also a backinglayer and an active agent-free pressure-sensitive adhesive layer andwhich is larger than the individual systems of buprenorphine-containingself-adhesive layer structure.
 67. Method in accordance with claim 66,wherein in step 1 buprenorphine is present in the form of buprenorphinebase and the carboxylic acid is levulinic acid and are suspended inethanol and subsequently combined with a polymer-basedpressure-sensitive adhesive based on polysiloxane in heptane to providethe buprenorphine-containing adhesive mixture or solution.
 68. Method oftreating pain in a patient by applying for about 168 hours on the skinof a patient a transdermal therapeutic system for the transdermaladministration of buprenorphine, comprising a buprenorphine-containingself-adhesive layer structure comprising A) a buprenorphine-impermeablebacking layer, and B) a buprenorphine-containing pressure-sensitiveadhesive layer on said buprenorphine-impermeable backing layer, theadhesive layer comprising a) at least one polymer-basedpressure-sensitive adhesive, b) an analgesically effective amount ofbuprenorphine base or a pharmaceutically acceptable salt thereof; and c)a carboxylic acid selected from the group consisting of oleic acid,linoleic acid and linolenic acid, levulinic acid and mixtures thereof,in an amount sufficient so that said analgesically effective amount ofbuprenorphine is solubilized therein to form a mixture, and thecarboxylic acid buprenorphine mixture forms dispersed deposits in thesaid pressure-sensitive adhesive, wherein said buprenorphine-containingpressure-sensitive adhesive layer is the skin contact layer. 69.Transdermal therapeutic system for administration of buprenorphine,comprising a buprenorphine-containing self-adhesive layer structurecomprising A) a buprenorphine-impermeable backing layer, and B) abuprenorphine-containing pressure-sensitive adhesive layer on saidbuprenorphine-impermeable backing layer, the adhesive layer comprisinga) at least one polymer-based pressure-sensitive adhesive, b) ananalgesically effective amount of buprenorphine base or apharmaceutically acceptable salt thereof, and c) a carboxylic acidselected from the group consisting of oleic acid, linoleic acid,linolenic acid, levulinic acid and mixtures thereof, in an amountsufficient so that said analgesically effective amount of buprenorphineis solubilized therein to form a mixture, and the carboxylic acidbuprenorphine mixture forms dispersed deposits in the saidpressure-sensitive adhesive, wherein said buprenorphine-containingpressure-sensitive adhesive layer is the skin contact layer for use in amethod of treating pain by applying said transdermal therapeutic systemfor about 168 hours on the skin of a patient.
 70. Transdermaltherapeutic system for the transdermal administration of buprenorphinebase, comprising a buprenorphine base-containing self-adhesive layerstructure comprising A) a buprenorphine base-impermeable backing layer,and B) a buprenorphine base-containing pressure-sensitive adhesive layeron said buprenorphine base-impermeable backing layer, the adhesive layercomprising a) at least one pressure-sensitive adhesive based onpolysiloxane, b) an analgesically effective amount of buprenorphinebase, and c) levulinic acid, in an amount sufficient so that saidanalgesically effective amount of buprenorphine base is solubilizedtherein to form a mixture, and the levulinic acid buprenorphine basemixture forms dispersed deposits in the said pressure-sensitiveadhesive, wherein said buprenorphine base-containing pressure-sensitiveadhesive layer is the skin contact layer.
 71. Method of treating pain ina patient by applying to the skin of said patient for about 168 hours atransdermal therapeutic system, comprising a buprenorphinebase-containing self-adhesive layer structure comprising A) abuprenorphine base-impermeable backing layer, and B) a buprenorphinebase-containing pressure-sensitive adhesive layer on said buprenorphinebase-impermeable backing layer, the adhesive layer comprising a) atleast one pressure-sensitive adhesive based on polysiloxane, b) ananalgesically effective amount of buprenorphine base, and c) levulinicacid, in an amount sufficient so that said analgesically effectiveamount of buprenorphine base is solubilized therein to form a mixture,and the levulinic acid buprenorphine base mixture forms disperseddeposits in the said pressure-sensitive adhesive, wherein saidbuprenorphine base-containing pressure-sensitive adhesive layer is theskin contact layer.
 72. Transdermal therapeutic system for thetransdermal administration of buprenorphine base, comprising abuprenorphine base-containing self-adhesive layer structure comprisingA) a buprenorphine base-impermeable backing layer, and B) abuprenorphine base-containing pressure-sensitive adhesive layer on saidbuprenorphine base-impermeable backing layer, the adhesive layercomprising a) at least one pressure-sensitive adhesive based onpolysiloxane, b) an analgesically effective amount of buprenorphinebase, and c) levulinic acid, in an amount sufficient so that saidanalgesically effective amount of buprenorphine base is solubilizedtherein to form a mixture, and the levulinic acid buprenorphine basemixture forms dispersed deposits in the said pressure-sensitiveadhesive, wherein said buprenorphine base-containing pressure-sensitiveadhesive layer is the skin contact layer for use in a method of treatingpain by applying said transdermal therapeutic system for about 168 hourson the skin of a patient.
 73. Transdermal therapeutic system for thetransdermal administration of buprenorphine, comprising abuprenorphine-containing self-adhesive layer structure comprising A) abuprenorphine-impermeable backing layer, and B) abuprenorphine-containing pressure-sensitive adhesive layer on saidbuprenorphine-impermeable backing layer, the adhesive layer comprisinga) at least one polymer-based pressure-sensitive adhesive, b) ananalgesically effective amount of buprenorphine base or apharmaceutically acceptable salt thereof, and c) a carboxylic acidselected from the group consisting of oleic acid, linoleic acid,linolenic acid, levulinic acid and mixtures thereof, in an amountsufficient so that said analgesically effective amount of buprenorphineis solubilized therein to form a mixture, and the carboxylic acidbuprenorphine solution forms dispersed deposits in the saidpressure-sensitive adhesive, wherein said buprenorphine-containingpressure-sensitive adhesive layer is the skin contact layer and containsmore than about 0.55 mg/cm² or more than 0.6 mg/cm² of buprenorphinebase or an equimolar amount of a pharmaceutically acceptable saltthereof.
 74. Method of treating pain in a patient by applying to theskin of said patient for about 168 hours a transdermal therapeuticsystem for the transdermal administration of buprenorphine, comprising abuprenorphine-containing self-adhesive layer structure comprising A) abuprenorphine-impermeable backing layer, and B) abuprenorphine-containing pressure-sensitive adhesive layer on saidbuprenorphine-impermeable backing layer, the adhesive layer comprisinga) at least one polymer-based pressure-sensitive adhesive, b) ananalgesically effective amount of buprenorphine base or apharmaceutically acceptable salt thereof, and c) a carboxylic acidselected from the group consisting of oleic acid, linoleic acid,linolenic acid, levulinic acid and mixtures thereof, in an amountsufficient so that said analgesically effective amount of buprenorphineis solubilized therein to form a mixture, and the carboxylic acidbuprenorphine solution forms dispersed deposits in the saidpressure-sensitive adhesive, wherein said buprenorphine-containingpressure-sensitive adhesive layer is the skin contact layer and containsmore than about 0.55 mg/cm² or more than 0.6 mg/cm² of buprenorphinebase or an equimolar amount of a pharmaceutically acceptable saltthereof.
 75. Transdermal therapeutic system for the transdermaladministration of buprenorphine, comprising a buprenorphine-containingself-adhesive layer structure comprising A) a buprenorphine-impermeablebacking layer, and B) a buprenorphine-containing pressure-sensitiveadhesive layer on said buprenorphine-impermeable backing layer, theadhesive layer comprising a) at least one polymer-basedpressure-sensitive adhesive, b) an analgesically effective amount ofbuprenorphine base or a pharmaceutically acceptable salt thereof, and c)a carboxylic acid selected from the group consisting of oleic acid,linoleic acid, linolenic acid, levulinic acid and mixtures thereof, inan amount sufficient so that said analgesically effective amount ofbuprenorphine is solubilized therein to form a mixture, and thecarboxylic acid buprenorphine solution forms dispersed deposits in thesaid pressure-sensitive adhesive, wherein said buprenorphine-containingpressure-sensitive adhesive layer is the skin contact layer and containsmore than about 0.55 mg/cm² or more than 0.6 mg/cm² of buprenorphinebase or an equimolar amount of a pharmaceutically acceptable saltthereof for use in a method of treating pain by applying saidtransdermal therapeutic system for about 168 hours on the skin of apatient.
 76. Transdermal therapeutic system for the transdermaladministration of buprenorphine base, comprising a buprenorphinebase-containing self-adhesive layer structure comprising A) abuprenorphine base-impermeable backing layer, and B) a buprenorphinebase-containing pressure-sensitive adhesive layer on said buprenorphinebase-impermeable backing layer, the adhesive layer comprising a) atleast one pressure-sensitive adhesive based on polysiloxanes, b) ananalgesically effective amount of buprenorphine base, and c) levulinicacid, in an amount sufficient so that said analgesically effectiveamount of buprenorphine base is solubilized therein to form a mixture,and the levulinic acid buprenorphine base mixture forms disperseddeposits in the said pressure-sensitive adhesive, wherein saidbuprenorphine base-containing pressure-sensitive adhesive layer is theskin contact layer and contains more than about 0.55 mg/cm² or more than0.6 mg/cm² of buprenorphine base.
 77. Method of treating pain in apatient by applying to the skin of said patient for about 168 hours atransdermal therapeutic system for the transdermal administration ofbuprenorphine base, comprising a buprenorphine base-containingself-adhesive layer structure comprising A) a buprenorphinebase-impermeable backing layer, and B) a buprenorphine base-containingpressure-sensitive adhesive layer on said buprenorphine base-impermeablebacking layer, the adhesive layer comprising a) at least onepressure-sensitive adhesive based on polysiloxanes, b) an analgesicallyeffective amount of buprenorphine base, and c) levulinic acid, in anamount sufficient so that said analgesically effective amount ofbuprenorphine base is solubilized therein to form a mixture, and thelevulinic acid buprenorphine base mixture forms dispersed deposits inthe said pressure-sensitive adhesive, wherein said buprenorphinebase-containing pressure-sensitive adhesive layer is the skin contactlayer and contains more than about 0.55 mg/cm² or more than 0.6 mg/cm²of buprenorphine base.
 78. Transdermal therapeutic system for thetransdermal administration of buprenorphine base, comprising abuprenorphine base-containing self-adhesive layer structure comprisingA) a buprenorphine base-impermeable backing layer, and B) abuprenorphine base-containing pressure-sensitive adhesive layer on saidbuprenorphine base-impermeable backing layer, the adhesive layercomprising a) at least one pressure-sensitive adhesive based onpolysiloxanes, b) an analgesically effective amount of buprenorphinebase, and c) levulinic acid, in an amount sufficient so that saidanalgesically effective amount of buprenorphine base is solubilizedtherein to form a mixture, and the levulinic acid buprenorphine basemixture forms dispersed deposits in the said pressure-sensitiveadhesive, wherein said buprenorphine base-containing pressure-sensitiveadhesive layer is the skin contact layer and contains more than about0.55 mg/cm² or more than 0.6 mg/cm² of buprenorphine base for use in amethod of treating pain by applying said transdermal therapeutic systemfor about 168 hours on the skin of a patient.
 79. A set of two to fivedifferent transdermal therapeutic systems for the transdermaladministration of buprenorphine base selected from five differenttransdermal therapeutic systems, a first, a second, a third, a forth anda fifth transdermal therapeutic system, each of the five differenttransdermal therapeutic systems comprising a buprenorphine-containingself-adhesive layer structure comprising A) a buprenorphinebase-impermeable backing layer, and B) a buprenorphine base-containingpressure-sensitive adhesive layer on said buprenorphine base-impermeablebacking layer, the adhesive layer comprising a) at least onepressure-sensitive adhesive based on polysiloxanes, b) an analgesicallyeffective amount of buprenorphine base, and c) levulinic acid, in anamount sufficient so that said analgesically effective amount ofbuprenorphine base is solubilized therein to form a mixture, and thelevulinic acid buprenorphine base mixture forms dispersed deposits inthe said pressure-sensitive adhesive, wherein, the first transdermaltherapeutic system provides a size of said buprenorphine-containingpressure-sensitive adhesive layer providing the area of release rangingfrom about 1 cm² to about 4.8 cm² and contains from about 1 mg to about4 mg buprenorphine base; the second transdermal therapeutic systemprovides a size of said buprenorphine-containing pressure-sensitiveadhesive layer providing the area of release ranging from about 3 cm² toabout 9.5 cm² and contains from about 3.5 mg to about 8 mg buprenorphinebase; and the third transdermal therapeutic system provides a size ofsaid buprenorphine-containing pressure-sensitive adhesive layerproviding the area of release ranging from about 6 cm² to about 19 cm²and contains from about 6.5 mg to about 16 mg buprenorphine base; andthe fourth transdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 12 cm² to about 28.5 cm² and containsfrom about 11.5 mg to about 24 mg buprenorphine base; and the fifthtransdermal therapeutic system provides a size of saidbuprenorphine-containing pressure-sensitive adhesive layer providing thearea of release ranging from about 16 cm² to about 38 cm² and containsfrom about 15 mg to about 32 mg buprenorphine base, wherein the fivedifferent transdermal therapeutic systems have increasing areas ofrelease and amounts of buprenorphine from the first to the fifthtransdermal therapeutic system for use in method of treating pain byapplying one of said transdermal therapeutic systems for about 168 hourson the skin of a patient.